ACE-Triggered Hypertension Incites Stroke: Genetic, Molecular, and Therapeutic Aspects

  • Kanika Vasudeva
  • Renuka Balyan
  • Anjana MunshiEmail author
Review Paper


Stroke is the second largest cause of death worldwide. Angiotensin converting enzyme (ACE) gene has emerged as an important player in the pathogenesis of hypertension and consequently stroke. It encodes ACE enzyme that converts the inactive decapeptide angiotensin I to active octapeptide, angiotensin II (Ang II). Dysregulation in the expression of ACE gene, on account of genetic variants or regulation by miRNAs, alters the levels of ACE in the circulation. Variable expression of ACE affects the levels of Ang II. Ang II acts through different signal transduction pathways via various tyrosine kinases (receptor/non-receptor) and protein serine/threonine kinases, initiating a downstream cascade of molecular events. In turn these activated molecular pathways might lead to hypertension and inflammation thereby resulting in cardiovascular and cerebrovascular diseases including stroke. In order to regulate the overexpression of ACE, many ACE inhibitors and blockers have been developed, some of which are still under clinical trials.


Stroke Genetic variants miRNAs Neurons Glial cells Vascular smooth muscle cells 



The authors are also grateful to the Central University of Punjab, Bathinda, India, for providing the academic, administrative, and infrastructural support to carry out this work. Ms. Kanika Vasudeva is grateful to University Grants Commission (UGC), India, for providing financial assistance in the form of UGC-NET, JRF.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abeywardena, M. Y., Leifert, W. R., Warnes, K. E., Varghese, J. N., & Head, R. J. (2009). Cardiovascular biology of interleukin-6. Current Pharmaceutical Design,15(15), 1809–1821.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Agarwal, D., Dange, R. B., Raizada, M. K., & Francis, J. (2013). Angiotensin II causes imbalance between pro-and anti-inflammatory cytokines by modulating GSK-3β in neuronal culture. British Journal of Pharmacology,169(4), 860–874.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Allen, A. M. (2002). Inhibition of the hypothalamic paraventricular nucleus in spontaneously hypertensive rats dramatically reduces sympathetic vasomotor tone. Hypertension,39(2), 275–280.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Arnold, J. M. O., Yusuf, S., Young, J., Mathew, J., Johnstone, D., Avezum, A., … Bosch, J. (2003). Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation, 107(9), 1284–1290.PubMedCrossRefPubMedCentralGoogle Scholar
  5. Barnes, P. J., & Karin, M. (1997). Nuclear factor-κB—A pivotal transcription factor in chronic inflammatory diseases. New England Journal of Medicine,336(15), 1066–1071.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Bátkai, S., & Thum, T. (2012). MicroRNAs in hypertension: Mechanisms and therapeutic targets. Current Hypertension Reports,14(1), 79–87.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Benjamin, E. J., Blaha, M. J., Chiuve, S. E., Cushman, M., Das, S. R., Deo, R., … Isasi, C. (2017). Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation, 135(10), e146–e603.Google Scholar
  8. Biancardi, V. C., Bomfim, G. F., Reis, W. L., Al-Gassimi, S., & Nunes, K. P. (2017). The interplay between Angiotensin II, TLR4 and hypertension. Pharmacological Research,120, 88–96.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Boettger, T., Beetz, N., Kostin, S., Schneider, J., Krüger, M., Hein, L., et al. (2009). Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. The Journal of Clinical Investigation,119(9), 2634–2647.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Böhm, M., Schumacher, H., Teo, K. K., Lonn, E. M., Mahfoud, F., Mann, J. F., … Sliwa, K. (2017). Achieved blood pressure and cardiovascular outcomes in high-risk patients: Results from ONTARGET and TRANSCEND trials. The Lancet, 389(10085), 2226–2237.CrossRefGoogle Scholar
  11. Booth, H. D., Hirst, W. D., & Wade-Martins, R. (2017). The role of astrocyte dysfunction in Parkinson’s disease pathogenesis. Trends in Neurosciences,40(6), 358–370.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Braga, V., Medeiros, I., Ribeiro, T., França-Silva, M., Botelho-Ono, M., & Guimarães, D. (2011). Angiotensin-II-induced reactive oxygen species along the SFO-PVN-RVLM pathway: Implications in neurogenic hypertension. Brazilian Journal of Medical and Biological Research,44(9), 871–876.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Brambilla, L., Martorana, F., & Rossi, D. (2013). Astrocyte signaling and neurodegeneration: New insights into CNS disorders. Prion,7(1), 28–36.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Campese, V. M., Shaohua, Y., & Huiquin, Z. (2005). Oxidative stress mediates angiotensin II–dependent stimulation of sympathetic nerve activity. Hypertension,46(3), 533–539.PubMedCrossRefPubMedCentralGoogle Scholar
  15. Cardinale, J. P., Sriramula, S., Mariappan, N., Agarwal, D., & Francis, J. (2012). Angiotensin II–induced hypertension is modulated by nuclear factor-κB in the paraventricular nucleus. Hypertension,59(1), 113–121.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Carmichael, C. Y., & Wainford, R. D. (2015). Hypothalamic signaling mechanisms in hypertension. Current Hypertension Reports,17(5), 39.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Castoldi, G., Di Gioia, C. R., Bombardi, C., Catalucci, D., Corradi, B., Gualazzi, M. G., … Condorelli, G. (2012). MiR-133a regulates collagen 1A1: Potential role of miR-133a in myocardial fibrosis in angiotensin II-dependent hypertension. Journal of cellular physiology, 227(2), 850–856.CrossRefGoogle Scholar
  18. Castoldi, G., di Gioia, C., Giollo, F., Carletti, R., Bombardi, C., Antoniotti, M., … Stella, A. (2016). Different regulation of miR-29a-3p in glomeruli and tubules in an experimental model of angiotensin II-dependent hypertension: Potential role in renal fibrosis. Clinical and Experimental Pharmacology and Physiology, 43(3), 335–342.PubMedCrossRefPubMedCentralGoogle Scholar
  19. Celiker, G., Can, U., Verdi, H., Yazici, A. C., Ozbek, N., & Atac, F. B. (2009). Prevalence of thrombophilic mutations and ACE I/D polymorphism in Turkish ischemic stroke patients. Clinical and Applied Thrombosis/Hemostasis,15(4), 415–420.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Chalmers, J., & MacMahon, S. (2003). Perindopril protection against Recurrent Stroke Study (PROGRESS): Interpretation and implementation. Journal of Hypertension,21, S9–S14.PubMedCrossRefPubMedCentralGoogle Scholar
  21. Chan, J. Y., Chen, W.-C., Lee, H.-Y., & Chan, S. H. (1998). Elevated Fos expression in the nucleus tractus solitarii is associated with reduced baroreflex response in spontaneously hypertensive rats. Hypertension,32(5), 939–944.PubMedCrossRefPubMedCentralGoogle Scholar
  22. Chen, Y.-C., Chang, K.-H., & Chen, C.-M. (2018). Genetic polymorphisms associated with spontaneous intracerebral hemorrhage. International Journal of Molecular Sciences,19(12), 3879.PubMedCentralCrossRefGoogle Scholar
  23. Chen, M. M., Lam, A., Abraham, J. A., Schreiner, G. F., & Joly, A. H. (2000). CTGF expression is induced by TGF-β in cardiac fibroblasts and cardiac myocytes: A potential role in heart fibrosis. Journal of Molecular and Cellular Cardiology,32(10), 1805–1819.PubMedCrossRefPubMedCentralGoogle Scholar
  24. Cheng, W.-H., Lu, P.-J., Ho, W.-Y., Tung, C.-S., Cheng, P.-W., Hsiao, M., et al. (2010). Angiotensin II inhibits neuronal nitric oxide synthase activation through the ERK1/2-RSK signaling pathway to modulate central control of blood pressure. Circulation Research,106(4), 788.PubMedCrossRefPubMedCentralGoogle Scholar
  25. Chengzhi, L., Li, W., Essackjee, A., Sherpa, N., & Di, L. (2012). Angiotensin-II induced reactive oxygen species: Implications in neurogenic hypertension. Journal of Hypertension,1, 106.Google Scholar
  26. Clark, M. A., & Gonzalez, N. (2007a). Angiotensin II stimulates rat astrocyte mitogen-activated protein kinase activity and growth through EGF and PDGF receptor transactivation. Regulatory Peptides,144(1–3), 115–122.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Clark, M. A., & Gonzalez, N. (2007b). Src and Pyk2 mediate angiotensin II effects in cultured rat astrocytes. Regulatory Peptides,143(1–3), 47–55.PubMedCrossRefPubMedCentralGoogle Scholar
  28. Clark, M. A., Guillaume, G., & Pierre-Louis, H. C. (2008). Angiotensin II induces proliferation of cultured rat astrocytes through c-Jun N-terminal kinase. Brain Research Bulletin,75(1), 101–106.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Clark, M., Landrum, M., & Tallant, E. (2001). Angiotensin II activates mitogen-activated protein kinases and stimulates growth in rat medullary astrocytes. Paper Presented at the Faseb Journal.Google Scholar
  30. Dahlöf, B., Devereux, R. B., Kjeldsen, S. E., Julius, S., Beevers, G., de Faire, U., … Lederballe-Pedersen, O. (2002). Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. The Lancet, 359(9311), 995–1003.CrossRefGoogle Scholar
  31. Dardiotis, E., Jagiella, J., Xiromerisiou, G., Dardioti, M., Vogiatzi, C., Urbanik, A., … Slowik, A. (2011). Angiotensin-converting enzyme tag single nucleotide polymorphisms in patients with intracerebral hemorrhage. Pharmacogenetics and Genomics, 21(3), 136–141.PubMedCrossRefPubMedCentralGoogle Scholar
  32. Das, S., Roy, S., Sharma, V., Kaul, S., Jyothy, A., & Munshi, A. (2015). Association of ACE gene I/D polymorphism and ACE levels with hemorrhagic stroke: Comparison with ischemic stroke. Neurological Sciences,36(1), 137–142.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Daub, H., Weiss, F. U., Wallasch, C., & Ullrich, A. (1996). Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature,379(6565), 557.PubMedCrossRefPubMedCentralGoogle Scholar
  34. Delaney, J., Chiarello, R., Villar, D., Kandalam, U., Castejon, A. M., & Clark, M. A. (2008). Regulation of c-fos, c-jun and c-myc gene expression by angiotensin II in primary cultured rat astrocytes: Role of ERK1/2 MAP kinases. Neurochemical Research,33(3), 545–550.PubMedCrossRefPubMedCentralGoogle Scholar
  35. Dennis, G. J. (2008). A haplotype analysis of the angiotensin converting enzyme gene in ischaemic stroke. Leicester: University of Leicester.Google Scholar
  36. Di Malta, C., Fryer, J. D., Settembre, C., & Ballabio, A. (2012). Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder. Proceedings of the National Academy of Sciences USA,109(35), E2334–E2342.CrossRefGoogle Scholar
  37. Dive, V., Cotton, J., Yiotakis, A., Michaud, A., Vassiliou, S., Jiracek, J., … Corvol, P. (1999). RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites. Proceedings of the National Academy of Sciences USA, 96(8), 4330–4335.CrossRefGoogle Scholar
  38. Domingues-Montanari, S., Fernandez-Cadenas, I., Del Rio-Espinola, A., Mendioroz, M., Ribo, M., Obach, V., … Corbeto, N. (2010). The I/D polymorphism of the ACE1 gene is not associated with ischaemic stroke in Spanish individuals. European Journal of Neurology, 17(11), 1390–1392.PubMedCrossRefPubMedCentralGoogle Scholar
  39. Domingues-Montanari, S., Hernandez-Guillamon, M., Fernandez-Cadenas, I., Mendioroz, M., Boada, M., Munuera, J., … Gutierrez, M. (2011). ACE variants and risk of intracerebral hemorrhage recurrence in amyloid angiopathy. Neurobiology of Aging, 32(3), 551. e513–551. e522.CrossRefGoogle Scholar
  40. Eguchi, S., & Inagami, T. (2000). Signal transduction of angiotensin II type 1 receptor through receptor tyrosine kinase. Regulatory Peptides,91(1–3), 13–20.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Eskildsen, T., Jeppesen, P., Schneider, M., Nossent, A., Sandberg, M., Hansen, P., … Rasmussen, L. (2013). Angiotensin II regulates microRNA-132/-212 in hypertensive rats and humans. International Journal of Molecular Sciences, 14(6), 11190–11207.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Fernandes, T., Hashimoto, N. Y., Magalhaes, F. C., Fernandes, F. B., Casarini, D. E., Carmona, A. K., … Oliveira, E. M. (2011). Aerobic exercise training–induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin II, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). Hypertension, 58(2), 182–189.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Ferrari, R. (2004). Preserving bradykinin or blocking angiotensin II: The cardiovascular dilemma. Dialogues in Cardiovascular Medicine,9, 71–92.Google Scholar
  44. Ferrario, C. M. (2002). Use of angiotensin II receptor blockers in animal models of atherosclerosis. American Journal of Hypertension,15(S1), 9S–13S.PubMedCrossRefPubMedCentralGoogle Scholar
  45. Ferrario, C. M. (2011). ACE 2: More of Ang 1-7 or less Ang II? Current Opinion in Nephrology and Hypertension,20(1), 1.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Frauman, A. G., Johnston, C. I., & Fabiani, M. E. (2001). Angiotensin receptors: Distribution, signalling and function. Clinical Science,100(5), 481–492.PubMedCrossRefPubMedCentralGoogle Scholar
  47. Gao, S., Liu, T.-W., Wang, Z., Jiao, Z.-Y., Cai, J., Chi, H.-J., et al. (2014). Downregulation of MicroRNA-19b contributes to angiotensin II-induced overexpression of connective tissue growth factor in cardiomyocytes. Cardiology,127(2), 114–120.PubMedCrossRefPubMedCentralGoogle Scholar
  48. Gormley, K., Bevan, S., & Markus, H. (2007). Polymorphisms in genes of the renin-angiotensin system and cerebral small vessel disease. Cerebrovascular Diseases,23(2–3), 148–155.PubMedCrossRefPubMedCentralGoogle Scholar
  49. Goyal, R., Goyal, D., Leitzke, A., Gheorghe, C. P., & Longo, L. D. (2010). Brain renin-angiotensin system: Fetal epigenetic programming by maternal protein restriction during pregnancy. Reproductive Sciences,17(3), 227–238.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Group, P. C. (2001). Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. The Lancet,358(9287), 1033–1041.CrossRefGoogle Scholar
  51. Higuchi, S., Ohtsu, H., Suzuki, H., Shirai, H., Frank, G. D., & Eguchi, S. (2007). Angiotensin II signal transduction through the AT1 receptor: Novel insights into mechanisms and pathophysiology. Clinical Science,112(8), 417–428.PubMedCrossRefPubMedCentralGoogle Scholar
  52. Hu, B., TaoSong, J., YanQu, H., LongBi, C., ZhenHuang, X., XinLiu, X., et al. (2014). Mechanical stretch suppresses microRNA-145 expression by activating extracellular signal-regulated kinase 1/2 and upregulating angiotensin-converting enzyme to alter vascular smooth muscle cell phenotype. PLoS ONE,9(5), e96338.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Huang, Y., Li, G., Lan, H., Zhao, G., & Huang, C. (2014). Angiotensin-converting enzyme insertion/deletion gene polymorphisms and risk of intracerebral hemorrhage: A meta-analysis of epidemiologic studies. Journal of the Renin-Angiotensin-Aldosterone System,15(1), 32–38.PubMedCrossRefPubMedCentralGoogle Scholar
  54. Hubert, C., Houot, A.-M., Corvol, P., & Soubrier, F. (1991). Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. Journal of Biological Chemistry, 266(23), 15377-15383.Google Scholar
  55. Jackson, K. L., Marques, F. Z., Nguyen-Huu, T.-P., Stevenson, E. R., Charchar, F. J., Davern, P. J., & Head, G. A. (2014). MicroRNA-181a mimic inhibits the renin-angiotensin system and attenuates hypertension in a neurogenic model of hypertension. Hypertension, 64(suppl_1), A038-A038.Google Scholar
  56. Jacob, H. J., Lindpaintner, K., Lincoln, S. E., Kusumi, K., Bunker, R. K., Mao, Y.-P., ... Lander, E. S. (1991). Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell,67(1), 213–224.PubMedCrossRefPubMedCentralGoogle Scholar
  57. Jeppesen, P. L., Christensen, G. L., Schneider, M., Nossent, A. Y., Jensen, H. B., Andersen, D. C., ... Sheikh, S. P. (2011). Angiotensin II type 1 receptor signalling regulates microRNA differentially in cardiac fibroblasts and myocytes. British Journal of Pharmacology,164(2), 394–404.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Jiang, L., Zhou, X., Yang, H., Guan, R., Xin, Y., Wang, J., ... Wang, J. (2013). ACE2-Ang-(1-7)-Mas axis in brain: A potential target for prevention and treatment of ischemic stroke. Current Neuropharmacology,11(2), 209–217.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Jiang, L., Zhou, X., Yang, H., Guan, R., Xin, Y., Wang, J.,… Wang, J. (2018). Upregulation of AT1 Receptor Mediates a Pressor Effect through ROS-SAPK/JNK Signaling in Glutamatergic Neurons of Rostral Ventrolateral Medulla in Rats with Stress-Induced Hypertension. Frontiers in physiology, 9.Google Scholar
  60. Jin, W., Reddy, M. A., Chen, Z., Putta, S., Lanting, L., Kato, M., ... Tangirala, R. K. (2012). Small RNA sequencing reveals microRNAs that modulate angiotensin II effects in vascular smooth muscle cells. Journal of Biological Chemistry,287(19), 15672–15683.PubMedCrossRefPubMedCentralGoogle Scholar
  61. Kalita, J., Somarajan, B. I., Kumar, B., Mittal, B., & Misra, U. K. (2011). A study of ACE and ADD1 polymorphism in ischemic and hemorrhagic stroke. Clinica Chimica Acta,412(7–8), 642–646.CrossRefGoogle Scholar
  62. Kandalam, U., & Clark, M. A. (2010). Angiotensin II activates JAK2/STAT3 pathway and induces interleukin-6 production in cultured rat brainstem astrocytes. Regulatory Peptides,159(1–3), 110–116.PubMedCrossRefPubMedCentralGoogle Scholar
  63. Kang, Y.-M., Ma, Y., Zheng, J.-P., Elks, C., Sriramula, S., Yang, Z.-M., et al. (2009). Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovascular Research,82(3), 503–512.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Kaul, S., & Munshi, A. (2012). Genetics of ischemic stroke: Indian perspective. Neurology India,60(5), 498.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Kemp, J. R., Unal, H., Desnoyer, R., Yue, H., Bhatnagar, A., & Karnik, S. S. (2014). Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin–angiotensin system. Journal of Molecular and Cellular Cardiology,75, 25–39.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Keramatipour, M., McConnell, R. S., Kirkpatrick, P., Tebbs, S., Furlong, R. A., & Rubinsztein, D. C. (2000). The ACE I allele is associated with increased risk for ruptured intracranial aneurysms. Journal of Medical Genetics,37(7), 498–500.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Khakh, B. S., Beaumont, V., Cachope, R., Munoz-Sanjuan, I., Goldman, S. A., & Grantyn, R. (2017). Unravelling and exploiting astrocyte dysfunction in Huntington’s disease. Trends in Neurosciences,40(7), 422–437.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Kim, V. N. (2005). MicroRNA biogenesis: Coordinated cropping and dicing. Nature Reviews Molecular Cell Biology,6(5), 376.PubMedCrossRefPubMedCentralGoogle Scholar
  69. Kim, C. W., Kumar, S., Son, D. J., Jang, I.-H., Griendling, K. K., & Jo, H. (2014). Prevention of abdominal aortic aneurysm by Anti–MicroRNA-712 or Anti–MicroRNA-205 in angiotensin II–infused mice. Arteriosclerosis, Thrombosis, and Vascular Biology,34(7), 1412–1421.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Kim-Mitsuyama, S., Izumi, Y., Izumiya, Y., Namba, M., Yoshida, K., Wake, R., ... Iwao, H. (2006). Dominant-negative c-Jun inhibits rat cardiac hypertrophy induced by angiotensin II and hypertension. Gene Therapy,13(4), 348.CrossRefGoogle Scholar
  71. Kohlstedt, K., Trouvain, C., Boettger, T., Shi, L., Fisslthaler, B., & Fleming, I. (2013). AMP-activated protein kinase regulates endothelial cell angiotensin-converting enzyme expression via p53 and the post-transcriptional regulation of microRNA-143/145. Circulation Research,112(8), 1150–1158.PubMedCrossRefPubMedCentralGoogle Scholar
  72. Kretzschmar, M., & Massagué, J. (1998). SMADs: Mediators and regulators of TGF-β signaling. Current Opinion in Genetics & Development,8(1), 103–111.CrossRefGoogle Scholar
  73. Krupinski, J., Kumar, P., Kumar, S., & Kaluza, J. (1996). Increased expression of TGF-β1 in brain tissue after ischemic stroke in humans. Stroke,27(5), 852–857.PubMedCrossRefPubMedCentralGoogle Scholar
  74. Kumar, A., Vivekanandhan, S., Srivastava, A., Tripathi, M., Padma Srivastava, M., Saini, N., ... Prasad, K. (2014). Association between angiotensin converting enzyme gene insertion/deletion polymorphism and ischemic stroke in North Indian population: A case–control study and meta-analysis. Neurological Research,36(9), 786–794.PubMedCrossRefPubMedCentralGoogle Scholar
  75. Lambert, D. W., Lambert, L. A., Clarke, N. E., Hooper, N. M., Porter, K. E., & Turner, A. J. (2014). Angiotensin-converting enzyme 2 is subject to post-transcriptional regulation by miR-421. Clinical Science,127(4), 243–249.PubMedCrossRefPubMedCentralGoogle Scholar
  76. Lanz, T. V., Ding, Z., Ho, P. P., Luo, J., Agrawal, A. N., Srinagesh, H., ... Wyss-Coray, T. (2010). Angiotensin II sustains brain inflammation in mice via TGF-β. The Journal of Clinical Investigation,120(8), 2782–2794.PubMedCrossRefPubMedCentralGoogle Scholar
  77. Lassègue, B., & Griendling, K. K. (2010). NADPH oxidases: Functions and pathologies in the vasculature. Arteriosclerosis, Thrombosis, and Vascular Biology,30(4), 653–661.PubMedCrossRefPubMedCentralGoogle Scholar
  78. Lee, Y., Kim, M., Han, J., Yeom, K. H., Lee, S., Baek, S. H., et al. (2004). MicroRNA genes are transcribed by RNA polymerase II. The EMBO journal,23(20), 4051–4060.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Li, Z., Bains, J. S., & Ferguson, A. V. (1993). Functional evidence that the angiotensin antagonist losartan crosses the blood-brain barrier in the rat. Brain Research Bulletin,30(1–2), 33–39.PubMedCrossRefPubMedCentralGoogle Scholar
  80. Lin, H., Pan, S., Meng, L., Zhou, C., Jiang, C., Ji, Z., ... Guo, H. (2017). MicroRNA-384-mediated Herpud1 upregulation promotes angiotensin II-induced endothelial cell apoptosis. Biochemical and Biophysical Research Communications,488(3), 453–460.PubMedCrossRefPubMedCentralGoogle Scholar
  81. Lonn, E. M., Bosch, J., López-Jaramillo, P., Zhu, J., Liu, L., Pais, P., ... Dans, A. (2016). Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. New England Journal of Medicine,374(21), 2009–2020.Google Scholar
  82. Lyle, A. N., & Griendling, K. K. (2006). Modulation of vascular smooth muscle signaling by reactive oxygen species. Physiology,21(4), 269–280.PubMedCrossRefPubMedCentralGoogle Scholar
  83. Malueka, R. G., Dwianingsih, E. K., Sutarni, S., Bawono, R. G., Bayuangga, H. F., Gofir, A., et al. (2018). The D allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is associated with worse functional outcome of ischaemic stroke. International Journal of Neuroscience,128(8), 697–704.PubMedCrossRefPubMedCentralGoogle Scholar
  84. Malueka, R. G., Dwianingsih, E. K., Sutarni, S., Gofir, A., & Setyopranoto, I. (2017). Association between ace gene polymorphism and functional outcome of ischemic stroke. Journal of the Neurological Sciences,381, 618.CrossRefGoogle Scholar
  85. Markoula, S., Giannopoulos, S., Kostoulas, C., Tatsioni, A., Bouba, I., Maranis, S.,… Kyritsis, A. P. (2011). Gender association of the angiotensin-converting enzyme gene with ischaemic stroke. Journal of the Renin-Angiotensin-Aldosterone System, 12(4), 510-515.PubMedCrossRefPubMedCentralGoogle Scholar
  86. Martínez-Rodríguez, N., Posadas-Romero, C., Villarreal-Molina, T., Vallejo, M., Del-Valle-Mondragón, L., Ramírez-Bello, J., ... Vargas-Alarcón, G. (2013). Single nucleotide polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with essential hypertension and increased ACE enzyme levels in Mexican individuals. PLoS ONE,8(5), e65700.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Matarin, M., Brown, W. M., Dena, H., Britton, A., De Vrieze, F. W., Brott, T. G., ... Chanock, S. J. (2009). Candidate gene polymorphisms for ischemic stroke. Stroke,40(11), 3436–3442.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Mengesha, H. G., Petrucka, P., Spence, C., & Tafesse, T. B. (2019). Effects of angiotensin converting enzyme gene polymorphism on hypertension in Africa: A meta-analysis and systematic review. PLoS ONE,14(2), e0211054.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Miller, A. J., & Arnold, A. C. (2019). The renin–angiotensin system in cardiovascular autonomic control: Recent developments and clinical implications. Clinical Autonomic Research,29(2), 231–243.PubMedCrossRefPubMedCentralGoogle Scholar
  90. Moore, J. P., Vinh, A., Tuck, K. L., Sakkal, S., Krishnan, S. M., Chan, C. T., ... Kemp-Harper, B. K. (2015). M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure. American Journal of Physiology-Heart and Circulatory Physiology,309(5), H906–H917.PubMedCrossRefPubMedCentralGoogle Scholar
  91. Munshi, A., Das, S., & Kaul, S. (2015). Genetic determinants in ischaemic stroke subtypes: Seven year findings and a review. Gene,555(2), 250–259.PubMedCrossRefPubMedCentralGoogle Scholar
  92. Munshi, A., & Kaul, S. (2010). Genetic basis of stroke: An overview. Neurology India,58(2), 185.PubMedCrossRefPubMedCentralGoogle Scholar
  93. Munshi, A., Sultana, S., Kaul, S., Reddy, B. P., Alladi, S., & Jyothy, A. (2008). Angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischemic stroke in a South Indian population. Journal of the Neurological Sciences,272(1–2), 132–135.PubMedCrossRefPubMedCentralGoogle Scholar
  94. Nemecz, M., Alexandru, N., Tanko, G., & Georgescu, A. (2016). Role of microRNA in endothelial dysfunction and hypertension. Current Hypertension Reports,18(12), 87.PubMedCrossRefPubMedCentralGoogle Scholar
  95. Ning, Q., & Jiang, X. (2013). Angiotensin II upregulated the expression of microRNA-224 but not microRNA-21 in adult rat cardiac fibroblasts. Biomedical reports,1(5), 776–780.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Ohkuma, T., Jun, M., Rodgers, A., Cooper, M. E., Glasziou, P., Hamet, P., ... Neal, B. (2019). Acute increases in serum creatinine after starting angiotensin-converting enzyme inhibitor-based therapy and effects of its continuation on major clinical outcomes in Type 2 diabetes mellitus: The ADVANCE Trial. Hypertension,73(1), 84–91.PubMedCrossRefPubMedCentralGoogle Scholar
  97. Pannu, H., Kim, D. H., Seaman, C. R., Van Ginhoven, G., Shete, S., & Milewicz, D. M. (2005). Lack of an association between the angiotensin-converting enzyme insertion/deletion polymorphism and intracranial aneurysms in a Caucasian population in the United States. Journal of Neurosurgery,103(1), 92–96.PubMedCrossRefPubMedCentralGoogle Scholar
  98. Peck, G., Smeeth, L., Whittaker, J., Casas, J. P., Hingorani, A., & Sharma, P. (2008). The genetics of primary haemorrhagic stroke, subarachnoid haemorrhage and ruptured intracranial aneurysms in adults. PLoS ONE,3(11), e3691.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Peña-Silva, R. A., & Heistad, D. D. (2015). Stages in discovery: ACE2 and stroke. Hypertension,66(1), 15.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Pera, J., Slowik, A., Dziedzic, T., Wloch, D., & Szczudlik, A. (2006). ACE I/D polymorphism in different etiologies of ischemic stroke. Acta Neurologica Scandinavica,114(5), 320–322.PubMedCrossRefPubMedCentralGoogle Scholar
  101. Peterson, M. C. (2005). Circulating transforming growth factor ß-1: A partial molecular explanation for associations between hypertension, diabetes, obesity, smoking and human disease involving fibrosis. Medical Science Monitor, 11(7), RA229–RA232.Google Scholar
  102. Peterson, J. R., Burmeister, M. A., Tian, X., Zhou, Y., Guruju, M. R., Stupinski, J. A., ... Davisson, R. L. (2009). Genetic silencing of Nox2 and Nox4 reveals differential roles of these NADPH oxidase homologues in the vasopressor and dipsogenic effects of brain angiotensin II. Hypertension,54(5), 1106–1114.PubMedPubMedCentralCrossRefGoogle Scholar
  103. Prabhakar, P., De, T., Nagaraja, D., & Christopher, R. (2014). Angiotensin-converting enzyme gene insertion/deletion polymorphism and small vessel cerebral stroke in Indian population. International Journal of Vascular Medicine, 1–4.Google Scholar
  104. Ruilope, L. M., Redón, J., & Schmieder, R. (2007). Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme. Vascular Health and Risk Management,3(1), 1.PubMedPubMedCentralGoogle Scholar
  105. Saavedra, J. M. (2005). Brain angiotensin II: New developments, unanswered questions and therapeutic opportunities. Cellular and Molecular Neurobiology,25(3–4), 485–512.PubMedCrossRefPubMedCentralGoogle Scholar
  106. Sacco, R. L., Kasner, S. E., Broderick, J. P., Caplan, L. R., Connors, J., Culebras, A., … Higashida, R. T. (2013). An updated definition of stroke for the 21st century: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 44(7), 2064–2089.PubMedCrossRefPubMedCentralGoogle Scholar
  107. Saito, Y., & Berk, B. C. (2001). Transactivation: A novel signaling pathway from angiotensin II to tyrosine kinase receptors. Journal of Molecular and Cellular Cardiology,33(1), 3–7.PubMedCrossRefPubMedCentralGoogle Scholar
  108. Santos, R. A., de Silva, A. C. S., Maric, C., Silva, D. M., Machado, R. P., de Buhr, I., … Bader, M. (2003). Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of the National Academy of Sciences USA, 100(14), 8258–8263.CrossRefGoogle Scholar
  109. Sayed-Tabatabaei, F., Oostra, B., Isaacs, A., Van Duijn, C., & Witteman, J. (2006). ACE polymorphisms. Circulation Research,98(9), 1123–1133.PubMedCrossRefPubMedCentralGoogle Scholar
  110. Schrader, J., Lüders, S., Kulschewski, A., Hammersen, F., Plate, K., Berger, J. r., … Group, M. S. (2005). Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: Principal results of a prospective randomized controlled study (MOSES). Stroke, 36(6), 1218–1224.PubMedCrossRefPubMedCentralGoogle Scholar
  111. Sharma, N. M., & Patel, K. P. (2017). Post-translational regulation of neuronal nitric oxide synthase: Implications for sympathoexcitatory states. Expert opinion on therapeutic targets,21(1), 11–22.PubMedCrossRefPubMedCentralGoogle Scholar
  112. Sica, D. A. (2010). The evolution of renin-angiotensin blockade: Angiotensin-converting enzyme inhibitors as the starting point. Current Hypertension Reports,12(2), 67–73.PubMedCrossRefPubMedCentralGoogle Scholar
  113. Sica, D. A. (2016). A Review of antihypertensive drugs and choosing the right antihypertensive for recurrent stroke prevention hypertension and stroke (pp. 245–257). New York: Springer.Google Scholar
  114. Slowik, A., Borratynska, A., Pera, J., Betlej, M., Dziedzic, T., Krzyszkowski, T., … Szczudlik, A. (2004). II genotype of the angiotensin-converting enzyme gene increases the risk for subarachnoid hemorrhage from ruptured aneurysm. Stroke, 35(7), 1594–1597.PubMedCrossRefPubMedCentralGoogle Scholar
  115. Smeda, J. S., VanVliet, B. N., & King, S. R. (1999). Stroke-prone spontaneously hypertensive rats lose their ability to auto-regulate cerebral blood flow prior to stroke. Journal of Hypertension,17(12), 1697–1705.PubMedCrossRefPubMedCentralGoogle Scholar
  116. Sriramula, S., Cardinale, J. P., Lazartigues, E., & Francis, J. (2011). ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension. Cardiovascular Research,92(3), 401–408.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Sriramula, S., Xia, H., Xu, P., & Lazartigues, E. (2015). Brain-targeted ACE2 overexpression attenuates neurogenic hypertension by inhibiting COX mediated inflammation. Hypertension,65(3), 577.PubMedCrossRefPubMedCentralGoogle Scholar
  118. Staalsø, J. M., Nielsen, M., Edsen, T., Koefoed, P., Springborg, J. B., Moltke, F. B., … Olsen, N. V. (2011). Common variants of the ACE gene and aneurysmal subarachnoid hemorrhage in a Danish population: A case-control study. Journal of Neurosurgical Anesthesiology, 23(4), 304–309.PubMedCrossRefPubMedCentralGoogle Scholar
  119. Sun, Y., Liu, Y., Watts, L. T., Sun, Q., Zhong, Z., Yang, G.-Y., & Bian, L. (2014). Correction: Genetic Associations of Angiotensin-Converting Enzyme with Primary Intracerebral Hemorrhage: A Meta-analysis. PloS one, 9(1).Google Scholar
  120. Taddei, S., & Bortolotto, L. (2016). Unraveling the pivotal role of bradykinin in ACE inhibitor activity. American Journal of Cardiovascular Drugs,16(5), 309–321.PubMedCrossRefPubMedCentralGoogle Scholar
  121. Tascilar, N., Dursun, A., Ankarali, H., Mungan, G., Ekem, S., & Baris, S. (2009). Angiotensin-converting enzyme insertion/deletion polymorphism has no effect on the risk of atherosclerotic stroke or hypertension. Journal of the Neurological Sciences,285(1–2), 137–141.PubMedCrossRefPubMedCentralGoogle Scholar
  122. ten Dijke, P., & Hill, C. S. (2004). New insights into TGF-β–Smad signalling. Trends in Biochemical Sciences,29(5), 265–273.PubMedCrossRefPubMedCentralGoogle Scholar
  123. Tsuda, K. (2012). Renin-angiotensin system and sympathetic neurotransmitter release in the central nervous system of hypertension. International journal of hypertension, 2012.Google Scholar
  124. Tuncer, N., Tuglular, S., Kılıç, G., Sazcı, A., Us, Ö., & Kara, İ. (2006). Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke. Journal of Clinical Neuroscience,13(2), 224–227.PubMedCrossRefPubMedCentralGoogle Scholar
  125. Villard, E., & Soubrier, F. (1996). Molecular biology and genetics of the angiotensin-I-converting enzyme: Potential implications in cardiovascular diseases. Cardiovascular Research,32(6), 999–1007.PubMedCrossRefPubMedCentralGoogle Scholar
  126. Villard, E., Tiret, L., Visvikis, S., Rakotovao, R., Cambien, F., & Soubrier, F. (1996). Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis. American Journal of Human Genetics,58(6), 1268.PubMedPubMedCentralGoogle Scholar
  127. Wang, X., & Abdel-Rahman, A. A. (2004). An association between ethanol-evoked enhancement of c-jun gene expression in the nucleus tractus solitarius and the attenuation of baroreflexes. Alcoholism: Clinical and Experimental Research,28(8), 1264–1272.CrossRefGoogle Scholar
  128. Wei, L. K., Au, A., Menon, S., Griffiths, L. R., Kooi, C. W., Irene, L., … Hassan, M. R. A. (2017). Polymorphisms of MTHFR, eNOS, ACE, AGT, ApoE, PON1, PDE4D, and ischemic stroke: Meta-analysis. Journal of Stroke and Cerebrovascular Diseases, 26(11), 2482–2493.PubMedCrossRefPubMedCentralGoogle Scholar
  129. Weigert, C., Brodbeck, K., Klopfer, K., Häring, H., & Schleicher, E. (2002). Angiotensin II induces human TGF-β1 promoter activation: Similarity to hyperglycaemia. Diabetologia,45(6), 890–898.PubMedCrossRefPubMedCentralGoogle Scholar
  130. Weir, M. R., & Dzau, V. J. (1999). The renin-angiotensin-aldosterone system: A specific target for hypertension management. American Journal of Hypertension,12(S9), 205S–213S.PubMedCrossRefPubMedCentralGoogle Scholar
  131. Wu, W.-H., Hu, C.-P., Chen, X.-P., Zhang, W.-F., Li, X.-W., Xiong, X.-M., et al. (2011). MicroRNA-130a mediates proliferation of vascular smooth muscle cells in hypertension. American Journal of Hypertension,24(10), 1087–1093.PubMedCrossRefPubMedCentralGoogle Scholar
  132. Yang, L.-x., Liu, G., Zhu, G.-f., Liu, H., Guo, R.-w., Qi, F., & Zou, J.-h. (2014). MicroRNA-155 inhibits angiotensin II-induced vascular smooth muscle cell proliferation. Journal of the Renin-Angiotensin-Aldosterone System, 15(2), 109-116.Google Scholar
  133. Yang, Y., Ago, T., Zhai, P., Abdellatif, M., & Sadoshima, J. (2011). Thioredoxin 1 negatively regulates angiotensin II–induced cardiac hypertrophy through upregulation of miR-98/let-7. Circulation Research,108(3), 305–313.PubMedCrossRefPubMedCentralGoogle Scholar
  134. Yang, X., Long, L., Southwood, M., Rudarakanchana, N., Upton, P. D., Jeffery, T. K., … Morrell, N. W. (2005). Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circulation Research, 96(10), 1053–1063.PubMedCrossRefPubMedCentralGoogle Scholar
  135. Yang, Y., Zhou, Y., Cao, Z., Tong, X. Z., Xie, H. Q., Luo, T., … Wang, H. Q. (2016). miR-155 functions downstream of angiotensin II receptor subtype 1 and calcineurin to regulate cardiac hypertrophy. Experimental and Therapeutic Medicine, 12(3), 1556–1562.PubMedPubMedCentralCrossRefGoogle Scholar
  136. Yazawa, H., Miyachi, M., Furukawa, M., Takahashi, K., Takatsu, M., Tsuboi, K., … Kato, Y. (2011). Angiotensin-converting enzyme inhibition promotes coronary angiogenesis in the failing heart of Dahl salt-sensitive hypertensive rats. Journal of Cardiac Failure, 17(12), 1041–1050.Google Scholar
  137. Yin, J.-X., Yang, R.-F., Li, S., Renshaw, A. O., Li, Y.-L., Schultz, H. D., et al. (2010). Mitochondria-produced superoxide mediates angiotensin II-induced inhibition of neuronal potassium current. American Journal of Physiology-Cell Physiology,298(4), C857–C865.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Yusuf, S., Sleight, P., Pogue, J. F., Bosch, J., Davies, R., & Dagenais, G. (2000). Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The New England Journal of Medicine,342(3), 145–153.PubMedCrossRefPubMedCentralGoogle Scholar
  139. Zhang, Y., Huang, X.-R., Wei, L.-H., Chung, A. C., Yu, C.-M., & Lan, H.-Y. (2014). miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling. Molecular Therapy,22(5), 974–985.PubMedPubMedCentralCrossRefGoogle Scholar
  140. Zhang, Z., Xu, G., Liu, D., Fan, X., Zhu, W., & Liu, X. (2012). Angiotensin-converting enzyme insertion/deletion polymorphism contributes to ischemic stroke risk: A meta-analysis of 50 case-control studies. PLoS ONE,7(10), e46495.PubMedPubMedCentralCrossRefGoogle Scholar
  141. Zhao, J., Qin, X., Li, S., & Zeng, Z. (2014). Association between the ACE I/D polymorphism and risk of ischemic stroke: An updated meta-analysis of 47,026 subjects from 105 case–control studies. Journal of the Neurological Sciences,345(1–2), 37–47.PubMedCrossRefPubMedCentralGoogle Scholar
  142. Zhao, Y., Wu, J., Zhang, M., Zhou, M., Xu, F., Zhu, X. ,… Yun, S. (2017). Angiotensin II induces calcium/calcineurin signaling and podocyte injury by downregulating microRNA-30 family members. Journal of Molecular Medicine, 95(8), 887–898.PubMedCrossRefPubMedCentralGoogle Scholar
  143. Zheng, L., Xu, C.-C., Chen, W.-D., Shen, W.-L., Ruan, C.-C., Zhu, L.-M., … Gao, P.-J. (2010). MicroRNA-155 regulates angiotensin II type 1 receptor expression and phenotypic differentiation in vascular adventitial fibroblasts. Biochemical and Biophysical Research Communications, 400(4), 483–488.PubMedCrossRefPubMedCentralGoogle Scholar
  144. Zhu, N., Zhang, D., Chen, S., Liu, X., Lin, L., Huang, X., … Yuan, W. (2011). Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. Atherosclerosis, 215(2), 286–293.PubMedCrossRefPubMedCentralGoogle Scholar
  145. Zimmerman, M. C., Lazartigues, E., Lang, J. A., Sinnayah, P., Ahmad, I. M., Spitz, D. R., et al. (2002). Superoxide mediates the actions of angiotensin II in the central nervous system. Circulation Research,91(11), 1038–1045.PubMedCrossRefPubMedCentralGoogle Scholar
  146. Zimmerman, M. C., Lazartigues, E., Sharma, R. V., & Davisson, R. L. (2004). Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system. Circulation Research,95(2), 210–216.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Human Genetics and Molecular MedicineCentral University of PunjabBathindaIndia

Personalised recommendations