Abstract
The renin–angiotensin system is involved in the regulation of various heart diseases. The present study aimed to determine the effects of angiotensin (Ang)-(3–7) on cardiac remodeling and its downstream signaling pathways in neonatal rat cardiomyocytes (NRCMs) and neonatal rat cardiac fibroblasts (NRCFs). The administration of Ang-(3–7) alleviated isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis of mice. ISO treatment increased the levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (β-MHC) in NRCMs, and reduced the levels of collagen I, collagen III, fibronectin, and alpha-smooth muscle actin (α-SMA) in NRCFs. These changes were inhibited by Ang-(3–7) administration. The levels of protein kinase A (PKA), phosphorylated phosphatidylinositol-3-kinase (p-PI3K), and phosphorylated protein kinase B (p-Akt) were increased in NRCMs and NRCFs treated with ISO. The increase of PKA, but not p-PI3K or p-Akt was attenuated by Ang-(3–7) treatment in NRCMs. The increases of p-PI3K and p-Akt, but not PKA were reversed by Ang-(3–7) treatment in NRCFs. Treatment with cAMP or PKA overexpression reversed the attenuating effects of Ang-(3–7) on ISO-induced hypertrophy of NRCMs. The administration of PI3K inhibitor or Akt inhibitor alleviated ISO-induced fibrosis of NRCFs. These results indicated that Ang-(3–7) could alleviate cardiac remodeling. The administration of Ang-(3–7) attenuated hypertrophy of NRCMs via inhibiting the cAMP/PKA signaling pathway, and alleviated fibrosis of NRCFs via inhibiting PI3K/Akt signaling pathway.
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Data availability
Data available with corresponding author.
Abbreviations
- Ang:
-
Angiotensin
- ANP:
-
Atrial natriuretic peptide
- BNP:
-
Brain natriuretic peptide
- BW:
-
Body weight
- HW:
-
Heart weight
- ISO:
-
Isoprenaline
- LV:
-
Left ventricular
- LVAWd:
-
LV anterior wall thickness in diastole
- LVAWs:
-
LV anterior wall thickness in systole
- LVPWd:
-
LV posterior wall thickness in diastole
- LVPWs:
-
LV posterior wall thickness in systole
- MHC:
-
Myosin heavy chain
- NRCF:
-
Neonatal rat cardiac fibroblast
- NRCM:
-
Neonatal rat cardiomyocyte
- PI3K:
-
Phosphatidylinositol-3-kinase
- PKA:
-
Protein kinase A
- RAAS:
-
Renin–angiotensin–aldosterone system
- SMA:
-
Smooth muscle actin
- TL:
-
Tibia length
References
Abeyrathna P, Su Y (2015) The critical role of Akt in cardiovascular function. Vascul Pharmacol 74:38–48. https://doi.org/10.1016/j.vph.2015.05.008
Andrade-Franze GMF, Pereira ED Jr, Yosten GLC, Samson WK, Menani JV, De Luca LA Jr, Andrade CAF (2021) Blockade of ERK1/2 activation with U0126 or PEP7 reduces sodium appetite and angiotensin II-induced pressor responses in spontaneously hypertensive rats. Peptides 136:170439. https://doi.org/10.1016/j.peptides.2020.170439
Asselin CY, Lam A, Cheung DYC, Eekhoudt CR, Zhu A, Mittal I, Mayba A, Solati Z, Edel A, Austria JA, Aukema HM, Ravandi A, Thliveris J, Singal PK, Pierce GN, Niraula S, Jassal DS (2020) The cardioprotective role of flaxseed in the prevention of doxorubicin- and trastuzumab-mediated cardiotoxicity in C57BL/6 mice. J Nutr 150(9):2353–2363. https://doi.org/10.1093/jn/nxaa144
Delaunay M, Osman H, Kaiser S, Diviani D (2019) The role of cyclic AMP signaling in cardiac fibrosis. Cells. https://doi.org/10.3390/cells9010069
Diez J, Gonzalez A, Kovacic JC (2020) Myocardial interstitial fibrosis in nonischemic heart disease, part 3/4: JACC focus seminar. J Am Coll Cardiol 75(17):2204–2218. https://doi.org/10.1016/j.jacc.2020.03.019
Ferreira PM, Souza Dos Santos RA, Campagnole-Santos MJ (2007) Angiotensin-(3–7) pressor effect at the rostral ventrolateral medulla. Regul Pept 141(1–3):168–174. https://doi.org/10.1016/j.regpep.2006.12.031
Gallo S, Vitacolonna A, Bonzano A, Comoglio P, Crepaldi T (2019) ERK: a key player in the pathophysiology of cardiac hypertrophy. Int J Mol Sci. https://doi.org/10.3390/ijms20092164
Gao RF, Li X, Xiang HY, Yang H, Lv CY, Sun XL, Chen HZ, Gao Y, Yang JS, Luo W, Yang YQ, Tang YH (2021) The covalent NLRP3-inflammasome inhibitor Oridonin relieves myocardial infarction induced myocardial fibrosis and cardiac remodeling in mice. Int Immunopharmacol 90:107133. https://doi.org/10.1016/j.intimp.2020.107133
Gong J, Shen Y, Li P, Zhao K, Chen X, Li Y, Sheng Y, Zhou B, Kong X (2019) Superoxide anions mediate the effects of angiotensin (1–7) analog, alamandine, on blood pressure and sympathetic activity in the paraventricular nucleus. Peptides 118:170101. https://doi.org/10.1016/j.peptides.2019.170101
Horodinschi RN, Bratu OG, Dediu GN, Pantea Stoian A, Motofei I, Diaconu CC (2020) Heart failure and chronic obstructive pulmonary disease: a review. Acta Cardiol 75(2):97–104. https://doi.org/10.1080/00015385.2018.1559485
Kittana N (2018) Angiotensin-converting enzyme 2-Angiotensin 1–7/1-9 system: novel promising targets for heart failure treatment. Fundam Clin Pharmacol 32(1):14–25. https://doi.org/10.1111/fcp.12318
Li C, Miao X, Wang S, Liu Y, Sun J, Liu Q, Cai L, Wang Y (2021) Elabela may regulate SIRT3-mediated inhibition of oxidative stress through Foxo3a deacetylation preventing diabetic-induced myocardial injury. J Cell Mol Med 25(1):323–332. https://doi.org/10.1111/jcmm.16052
Lijnen PJ, van Pelt JF, Fagard RH (2012) Stimulation of reactive oxygen species and collagen synthesis by angiotensin II in cardiac fibroblasts. Cardiovasc Ther 30(1):e1-8. https://doi.org/10.1111/j.1755-5922.2010.00205.x
Liu C, Yang CX, Chen XR, Liu BX, Li Y, Wang XZ, Sun W, Li P, Kong XQ (2018) Alamandine attenuates hypertension and cardiac hypertrophy in hypertensive rats. Amino Acids 50(8):1071–1081. https://doi.org/10.1007/s00726-018-2583-x
Lyu L, Chen J, Wang W, Yan T, Lin J, Gao H, Li H, Lv R, Xu F, Fang L, Chen Y (2021) Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress. J Cell Mol Med. https://doi.org/10.1111/jcmm.16304
Nehme A, Zouein FA, Zayeri ZD, Zibara K (2019) An update on the tissue renin angiotensin system and its role in physiology and pathology. J Cardiovasc Dev Dis. https://doi.org/10.3390/jcdd6020014
Ngoh GA, Watson LJ, Facundo HT, Jones SP (2011) Augmented O-GlcNAc signaling attenuates oxidative stress and calcium overload in cardiomyocytes. Amino Acids 40(3):895–911. https://doi.org/10.1007/s00726-010-0728-7
Puhl SL, Weeks KL, Guran A, Ranieri A, Boknik P, Kirchhefer U, Muller FU, Avkiran M (2019) Role of type 2A phosphatase regulatory subunit B56alpha in regulating cardiac responses to beta-adrenergic stimulation in vivo. Cardiovasc Res 115(3):519–529. https://doi.org/10.1093/cvr/cvy230
Rai V, Sharma P, Agrawal S, Agrawal DK (2017) Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research. Mol Cell Biochem 424(1–2):123–145. https://doi.org/10.1007/s11010-016-2849-0
Raupp D, Fernandes RS, Antunes KH, Perin FA, Rigatto K (2020) Impact of angiotensin II type 1 and G-protein-coupled Mas receptor expression on the pulmonary performance of patients with idiopathic pulmonary fibrosis. Peptides 133:170384. https://doi.org/10.1016/j.peptides.2020.170384
Ren X, Zhang F, Zhao M, Zhao Z, Sun S, Fraidenburg DR, Tang H, Han Y (2017) Angiotensin-(1–7) in paraventricular nucleus contributes to the enhanced cardiac sympathetic afferent reflex and sympathetic activity in chronic heart failure rats. Cell Physiol Biochem 42(6):2523–2539. https://doi.org/10.1159/000480214
Saleem N, Prasad A, Goswami SK (2018) Apocynin prevents isoproterenol-induced cardiac hypertrophy in rat. Mol Cell Biochem 445(1–2):79–88. https://doi.org/10.1007/s11010-017-3253-0
Samak M, Fatullayev J, Sabashnikov A, Zeriouh M, Schmack B, Farag M, Popov AF, Dohmen PM, Choi YH, Wahlers T, Weymann A (2016) Cardiac hypertrophy: an introduction to molecular and cellular basis. Med Sci Monit Basic Res 22:75–79. https://doi.org/10.12659/MSMBR.900437
Shah A, Gul R, Yuan K, Gao S, Oh YB, Kim UH, Kim SH (2010) Angiotensin-(1–7) stimulates high atrial pacing-induced ANP secretion via Mas/PI3-kinase/Akt axis and Na+/H+ exchanger. Am J Physiol Heart Circ Physiol 298(5):H1365-1374. https://doi.org/10.1152/ajpheart.00608.2009
Silva MM, de Souza-Neto FP, Jesus ICG, Goncalves GK, Santuchi MC, Sanches BL, de Alcantara-Leonidio TC, Melo MB, Vieira MAR, Guatimosim S, Santos RAS, da Silva RF (2021) Alamandine improves cardiac remodeling induced by transverse aortic constriction in mice. Am J Physiol Heart Circ Physiol 320(1):H352–H363. https://doi.org/10.1152/ajpheart.00328.2020
Soltani Hekmat A, Javanmardi K, Tavassoli A, Gholampour Y (2020) Angiotensin (1–7) and apelin co-therapy: new strategy for heart failure treatment of rats. Anatol J Cardiol 23(4):209–217. https://doi.org/10.14744/AnatolJCardiol.2019.40072
Stoyell-Conti FF, Chabbra A, Puthentharayil J, Rigatto K, Speth RC (2021) Chronic administration of pharmacological doses of angiotensin 1–7 and iodoangiotensin 1–7 has minimal effects on blood pressure, heart rate, and cognitive function of spontaneously hypertensive rats. Physiol Rep 9(7):e14812. https://doi.org/10.14814/phy2.14812
Sun TL, Li WQ, Tong XL, Liu XY, Zhou WH (2021a) Xanthohumol attenuates isoprenaline-induced cardiac hypertrophy and fibrosis through regulating PTEN/AKT/mTOR pathway. Eur J Pharmacol 891:173690. https://doi.org/10.1016/j.ejphar.2020.173690
Sun Z, Zhang L, Li L, Shao C, Liu J, Zhou M, Wang Z (2021b) Galectin-3 mediates cardiac remodeling caused by impaired glucose and lipid metabolism through inhibiting two pathways of activating Akt. Am J Physiol Heart Circ Physiol 320(1):H364–H380. https://doi.org/10.1152/ajpheart.00523.2020
Takano H, Zou Y, Akazawa H, Toko H, Mizukami M, Hasegawa H, Asakawa M, Nagai T, Komuro I (2002) Inhibitory molecules in signal transduction pathways of cardiac hypertrophy. Hypertens Res 25(4):491–498. https://doi.org/10.1291/hypres.25.491
Wang L, Liu C, Chen X, Li P (2019) Alamandine attenuates longterm hypertensioninduced cardiac fibrosis independent of blood pressure. Mol Med Rep 19(6):4553–4560. https://doi.org/10.3892/mmr.2019.10167
Xu CN, Kong LH, Ding P, Liu Y, Fan ZG, Gao EH, Yang J, Yang LF (2020) Melatonin ameliorates pressure overload-induced cardiac hypertrophy by attenuating Atg5-dependent autophagy and activating the Akt/mTOR pathway. Biochim Biophys Acta Mol Basis Dis 1866(10):165848. https://doi.org/10.1016/j.bbadis.2020.165848
Xu H, An X, Tian J, Fu M, Wang Q, Li C, He X, Niu L (2021) Angiotensin-(1–7) protects against sepsis-associated left ventricular dysfunction induced by lipopolysaccharide. Peptides 144:170612. https://doi.org/10.1016/j.peptides.2021.170612
Yang L, Huang Y, He Q (2019) Regulation of angiotensin-converting enzyme 2-angiotensin (1–7)-Mas axis provides a new target for the treatment of cardiac remodeling and heart failure. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 31(11):1425–1428. https://doi.org/10.3760/cma.j.issn.2095-4352.2019.11.022
Yang C, Wu X, Shen Y, Liu C, Kong X, Li P (2020) Alamandine attenuates angiotensin II-induced vascular fibrosis via inhibiting p38 MAPK pathway. Eur J Pharmacol 883:173384. https://doi.org/10.1016/j.ejphar.2020.173384
Yoshida T, Yamashita M, Horimai C, Hayashi M (2014) Kruppel-like factor 4 protein regulates isoproterenol-induced cardiac hypertrophy by modulating myocardin expression and activity. J Biol Chem 289(38):26107–26118. https://doi.org/10.1074/jbc.M114.582809
Yurista SR, Matsuura TR, Sillje HHW, Nijholt KT, McDaid KS, Shewale SV, Leone TC, Newman JC, Verdin E, van Veldhuisen DJ, de Boer RA, Kelly DP, Westenbrink BD (2021) Ketone ester treatment improves cardiac function and reduces pathologic remodeling in preclinical models of heart failure. Circ Heart Fail 14(1):e007684. https://doi.org/10.1161/CIRCHEARTFAILURE.120.007684
Zhang J, Wei X, Zhang W, Wang F, Li Q (2020) MiR-326 targets MDK to regulate the progression of cardiac hypertrophy through blocking JAK/STAT and MAPK signaling pathways. Eur J Pharmacol 872:172941. https://doi.org/10.1016/j.ejphar.2020.172941
Zhang X, Ke PX, Yuan X, Zhang GP, Chen WL, Zhang GS (2021) Forskolin protected against streptozotocin-induced diabetic cardiomyopathy via inhibition of oxidative stress and cardiac fibrosis in mice. Biomed Res Int 2021:8881843. https://doi.org/10.1155/2021/8881843
Zheng J, Tian J, Wang S, Hu P, Wu Q, Shan X, Zhao P, Zhang C, Guo W, Xu M, Chen H, Lu R (2020) Stachydrine hydrochloride suppresses phenylephrine-induced pathological cardiac hypertrophy by inhibiting the calcineurin/nuclear factor of activated T-cell signalling pathway. Eur J Pharmacol 883:173386. https://doi.org/10.1016/j.ejphar.2020.173386
Zhou L, Ma B, Han X (2016) The role of autophagy in angiotensin II-induced pathological cardiac hypertrophy. J Mol Endocrinol 57(4):R143–R152. https://doi.org/10.1530/JME-16-0086
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YZ performed the study, and critically revised the manuscript. ZS analyzed the data and drafted the manuscript. AL conceived and designed the study, and revised manuscript. All authors read and approved the final manuscript.
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All procedures performed in studies involving animals were in accordance with the ethical standards of Binhai County People's Hospital in which the studies were conducted.
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726_2021_3074_MOESM1_ESM.tif
Supplementary file1 Figure S1. Effects of angiotensin (Ang)-(3-7) on ejection fraction (EF) and fractional shortening (FS). There is no significance between the four groups. Values represent mean ± SEM. *p < 0.05 versus Saline group; #p < 0.05 versus ISO group. n = 8 for each group. (TIF 50 KB)
726_2021_3074_MOESM2_ESM.tif
Supplementary file2 Figure S2. Effects of angiotensin (Ang)-(3-7) on isoprenaline (ISO)-induced hypertension. Ang-(3-7) attenuated the increases of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean artery pressure (MAP) of mice treated with ISO. Values represent mean ± SEM. *p < 0.05 versus Saline group; #p < 0.05 versus ISO group. n = 8 for each group. (TIF 78 KB)
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Zhang, Y., Shang, Z. & Liu, A. Angiotensin-(3–7) alleviates isoprenaline-induced cardiac remodeling via attenuating cAMP-PKA and PI3K/Akt signaling pathways. Amino Acids 53, 1533–1543 (2021). https://doi.org/10.1007/s00726-021-03074-9
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DOI: https://doi.org/10.1007/s00726-021-03074-9