Skip to main content

Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease

Abstract

Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1–7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2+/+ (wildtype) and ACE2+/− (heterozygote) mice. Pressure overload in ACE2+/− mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2+/− cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2+/− hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2+/− mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2+/− vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion.

Key message

  • Heart disease in humans with idiopathic dilated cardiomyopathy is associated with a partial loss of ACE2.

  • Heterozygote female ACE2 mutant mice showed enhanced susceptibility to pressure overload-induced heart disease.

  • Heterozygote female ACE2 mutant mice showed enhanced susceptibility to Ang II-induced heart and vascular diseases.

  • Partial loss of ACE2 is sufficient to enhance the susceptibility to heart disease.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Weber KT, Brilla CG (1991) Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 83:1849–1865

    CAS  PubMed  Article  Google Scholar 

  2. Kim S, Iwao H (2000) Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 52:11–34

    CAS  PubMed  Google Scholar 

  3. Mehta PK, Griendling KK (2007) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292:C82–C97

    CAS  PubMed  Article  Google Scholar 

  4. Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y et al (2002) Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417:822–828

    CAS  PubMed  Article  Google Scholar 

  5. Oudit GY, Kassiri Z, Patel MP, Chappell M, Butany J, Backx PH, Tsushima RG, Scholey JW, Khokha R, Penninger JM (2007) Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovasc Res 75:29–39

    CAS  PubMed  Article  Google Scholar 

  6. Zhong J, Basu R, Guo D, Chow FL, Byrns S, Schuster M, Loibner H, Wang XH, Penninger JM, Kassiri Z et al (2010) Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation 122:717–728

    CAS  PubMed  Article  Google Scholar 

  7. Bodiga S, Zhong JC, Wang W, Basu R, Lo J, Liu GC, Guo D, Holland SM, Scholey JW, Penninger JM et al (2011) Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47phox NADPH oxidase subunit. Cardiovasc Res 91:151–161

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R et al (2000) A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 87:E1–E9

    CAS  PubMed  Article  Google Scholar 

  9. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ (2000) A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275:33238–33243

    CAS  PubMed  Article  Google Scholar 

  10. Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM (2004) Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 43:970–976

    CAS  PubMed  Article  Google Scholar 

  11. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI, Gallagher PE (2005) Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 111:2605–2610

    CAS  PubMed  Article  Google Scholar 

  12. Benter IF, Yousif MH, Anim JT, Cojocel C, Diz DI (2006) Angiotensin-(1–7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME. Am J Physiol Heart Circ Physiol 290:H684–H691

    CAS  PubMed  Article  Google Scholar 

  13. Mercure C, Yogi A, Callera GE, Aranha AB, Bader M, Ferreira AJ, Santos RA, Walther T, Touyz RM, Reudelhuber TL (2008) Angiotensin(1–7) blunts hypertensive cardiac remodeling by a direct effect on the heart. Circ Res 103:1319–1326

    CAS  PubMed  Article  Google Scholar 

  14. Kostenis E, Milligan G, Christopoulos A, Sanchez-Ferrer CF, Heringer-Walther S, Sexton PM, Gembardt F, Kellett E, Martini L, Vanderheyden P et al (2005) G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor. Circulation 111:1806–1813

    CAS  PubMed  Article  Google Scholar 

  15. Castro CH, Santos RA, Ferreira AJ, Bader M, Alenina N, Almeida AP (2005) Evidence for a functional interaction of the angiotensin-(1–7) receptor Mas with AT1 and AT2 receptors in the mouse heart. Hypertension 46:937–942

    PubMed  Article  Google Scholar 

  16. Grobe JL, Mecca AP, Lingis M, Shenoy V, Bolton TA, Machado JM, Speth RC, Raizada MK, Katovich MJ (2007) Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1–7). Am J Physiol Heart Circ Physiol 292:H736–H742

    CAS  PubMed  Article  Google Scholar 

  17. Mori J, Patel VB, Abo Alrob O, Basu R, Altamimi T, Desaulniers J, Wagg CS, Kassiri Z, Lopaschuk GD, Oudit GY (2014) Angiotensin 1–7 ameliorates diabetic cardiomyopathy and diastolic dysfunction in db/db mice by reducing lipotoxicity and inflammation. Circ Heart Fail 7: doi: 10.1161/CIRCHEARTFAILURE.113.000672

  18. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM (2002) Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 105:293–296

    CAS  PubMed  Article  Google Scholar 

  19. Byrne JA, Grieve DJ, Bendall JK, Li JM, Gove C, Lambeth JD, Cave AC, Shah AM (2003) Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy. Circ Res 93:802–805

    CAS  PubMed  Article  Google Scholar 

  20. Kassiri Z, Zhong J, Guo D, Basu R, Wang X, Liu PP, Scholey JW, Penninger JM, Oudit GY (2009) Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction. Circ Heart Fail 2:446–455

    CAS  PubMed  Article  Google Scholar 

  21. Patel VB, Bodiga S, Basu R, Das SK, Wang W, Wang Z, Lo J, Grant MB, Zhong J, Kassiri Z et al (2012) Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: a critical role of the angiotensin II/AT1 receptor axis. Circ Res 110:1322–1335

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  22. Guo D, Kassiri Z, Basu R, Chow FL, Kandalam V, Damilano F, Liang W, Izumo S, Hirsch E, Penninger JM et al (2010) Loss of PI3K{gamma} enhances cAMP-dependent MMP remodeling of the myocardial N-cadherin adhesion complexes and extracellular matrix in response to early biomechanical stress. Circ Res 107:1275–1289

    CAS  PubMed  Article  Google Scholar 

  23. Patel VB, Wang Z, Fan D, Zhabyeyev P, Basu R, Das SK, Wang W, Desaulniers J, Holland SM, Kassiri Z et al (2013) Loss of p47phox subunit enhances susceptibility to biomechanical stress and heart failure because of dysregulation of cortactin and actin filaments. Circ Res 112:1542–1556

    CAS  PubMed  Article  Google Scholar 

  24. Zhong J, Guo D, Chen CB, Wang W, Schuster M, Loibner H, Penninger JM, Scholey JW, Kassiri Z, Oudit GY (2011) Prevention of angiotensin II-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2. Hypertension 57:314–322

    CAS  PubMed  Article  Google Scholar 

  25. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L (1990) Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 82:1730–1736

    CAS  PubMed  Article  Google Scholar 

  26. Serneri GG, Boddi M, Cecioni I, Vanni S, Coppo M, Papa ML, Bandinelli B, Bertolozzi I, Polidori G, Toscano T et al (2001) Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function. Circ Res 88:961–968

    CAS  PubMed  Article  Google Scholar 

  27. Li JM, Shah AM (2003) Mechanism of endothelial cell NADPH oxidase activation by angiotensin II. Role of the p47phox subunit. J Biol Chem 278:12094–12100

    CAS  PubMed  Article  Google Scholar 

  28. Li JM, Wheatcroft S, Fan LM, Kearney MT, Shah AM (2004) Opposing roles of p47phox in basal versus angiotensin II-stimulated alterations in vascular O2- production, vascular tone, and mitogen-activated protein kinase activation. Circulation 109:1307–1313

    CAS  PubMed  Article  Google Scholar 

  29. Kim MA, Yang D, Kida K, Molotkova N, Yeo SJ, Varki N, Iwata M, Dalton ND, Peterson KL, Siems WE et al (2010) Effects of ACE2 inhibition in the post-myocardial infarction heart. J Card Fail 16:777–785

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  30. Yamamoto K, Ohishi M, Katsuya T, Ito N, Ikushima M, Kaibe M, Tatara Y, Shiota A, Sugano S, Takeda S et al (2006) Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension 47:718–726

    CAS  PubMed  Article  Google Scholar 

  31. Patel VB, Clarke N, Wang Z, Fan D, Parajuli N, Basu R, Putko B, Kassiri Z, Turner AJ, Oudit GY (2014) Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS. J Mol Cell Cardiol 66:167–176

    CAS  PubMed  Article  Google Scholar 

  32. Burrell LM, Risvanis J, Kubota E, Dean RG, MacDonald PS, Lu S, Tikellis C, Grant SL, Lew RA, Smith AI et al (2005) Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J 26:369–375, discussion 322-364

    CAS  PubMed  Article  Google Scholar 

  33. Patel SK, Wai B, Ord M, MacIsaac RJ, Grant S, Velkoska E, Panagiotopoulos S, Jerums G, Srivastava PM, Burrell LM (2012) Association of ACE2 genetic variants with blood pressure, left ventricular mass, and cardiac function in Caucasians with type 2 diabetes. Am J Hypertens 25:216–222

    CAS  PubMed  Article  Google Scholar 

  34. Tallant EA, Ferrario CM, Gallagher PE (2005) Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol 289:H1560–H1566

    CAS  PubMed  Article  Google Scholar 

  35. Takimoto E, Kass DA (2007) Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 49:241–248

    CAS  PubMed  Article  Google Scholar 

  36. Zile MR, Brutsaert DL (2002) New concepts in diastolic dysfunction and diastolic heart failure: part II: causal mechanisms and treatment. Circulation 105:1503–1508

    PubMed  Article  Google Scholar 

  37. Borlaug BA, Lam CS, Roger VL, Rodeheffer RJ, Redfield MM (2009) Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol 54:410–418

    PubMed Central  PubMed  Article  Google Scholar 

  38. Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600

    CAS  PubMed  Article  Google Scholar 

  39. Koka V, Huang XR, Chung AC, Wang W, Truong LD, Lan HY (2008) Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am J Pathol 172:1174–1183

    CAS  PubMed Central  PubMed  Article  Google Scholar 

Download references

Acknowledgments

Gavin Y. Oudit is a Clinician-Investigator of the Alberta Innovates – Health Solutions, Distinguish Clinician Scientist of the Heart and Stroke Foundation of Canada and Canadian Institutes of Health Research, and Canada Research Chair in Heart Failure. Vaibhav B. Patel is supported by Alberta Innovates - Health Solutions and Heart and Stroke Foundation of Canada Fellowship. Nirmal Parajuli is supported by Heart and Stroke Foundation of Canada Fellowship.

Conflict of Interest

None declared.

Funding

This work was supported by the Canadian Institutes of Health Research and Alberta Innovates – Health Solutions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gavin Y. Oudit.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 183 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Patel, V.B., Parajuli, N. et al. Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease. J Mol Med 92, 847–858 (2014). https://doi.org/10.1007/s00109-014-1149-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-014-1149-y

Keywords

  • Renin-angiotensin system
  • Angiotensin-converting enzyme 2
  • NADPH oxidase
  • Heart failure
  • Sex