Onset of Experimental Severe Cardiac Fibrosis Is Mediated by Overexpression of Angiotensin-Converting Enzyme 2

Abstract

Abstract-Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis. (Hypertension. 2009;53:694-700.)Key Words: ACE2 Ⅲ gene delivery Ⅲ adeno-associated virus Ⅲ hypertension Ⅲ myocardium O veractivity of the renin-angiotensin (Ang) system plays a fundamental role in the pathophysiology of hypertension and progression of heart failure. 1 Ang-converting enzyme (ACE) 2 is a recently identified homologue of ACE, and their catalytic domains share 42% amino acid identity. 2-4 ACE2 expression is restricted to the heart, kidney, and testis. 2,5 After myocardial infarction, increased ACE2 expression in the heart localized to vascular endothelium, smooth muscle, and cardiomyocytes in both rats and humans. 6 Unlike ACE, ACE2 functions as a carboxypeptidase rather than a dipeptidyl carboxypeptidase 5 and counterbalances the vasopressor effects of ACE. 7 ACE2 primarily hydrolyzes Ang II and, less efficiently, Ang I, 2 resulting in Ang 1-7 and Ang 1-9. Ang 1-9 is further hydrolyzed to Ang 1-7 by the actions of ACE. 5 ACE inhibitors and Ang II receptor blockers are effective drugs for the treatment of cardiovascular diseases, as a result of blocking the vasoconstrictor, hypertrophic, and proinflammatory actions of Ang II. 8 -11 Thus, ACE2 may play a pivotal role in the renin-Ang system by reducing concentrations of Ang II and raising levels of Ang 1-7. 12,13 Therefore, manipulation of ACE2 activity has potential therapeutic use. However, ACE2 knockout mice have been associated with severe contractile dysfunction 14 or, conversely, with no observed effects on cardiac dimension or function. 15 Overexpression of ACE2 by local delivery of lentivirus in the hearts of spontaneously hypertensive rats attenuated high blood pressure (BP) and perivascular fibrosis, reduced left ventricular (LV) wall thickness, and increased LV end diastolic and end systolic diameters. 16 Conversely, transgenic overex...

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

“…Thus, the beneficial effects of ACE2 observed in this study are most likely attributable to the net effect of decreased local Ang II level and increased local Ang-(1-7) level. Recent studies found that long-term ACE2 overexpression or Ang-(1-7) injection accelerated myocardial fibrosis or diabetic nephropathy (7,39,40). In this study, the outcome of ACE2 overexpression was assessed 4 weeks after gene transfer, and no detrimental effects were found, suggesting that our gene therapy offers a safe approach.…”

Angiotensin-(1–7) and angiotensin-(1–9): function in cardiac and vascular remodelling

“…These studies suggest a protective role for ACE2 in cardiac remodelling through reduced AngII production. However, other studies have shown the opposite in that overexpression of ACE2 is potentially associated with a worsened cardiac phenotype [48,49]. This phenomenon could be due to supraphysiological levels of expression at specific unwanted sites and therefore further studies are required to address this conflicting data.…”

Angiotensin-(1–7) Dose-Dependently Inhibits Atherosclerotic Lesion Formation and Enhances Plaque Stability by Targeting Vascular Cells

“…8 Despite these research efforts, several key issues remain unsolved. First, because the half-life of Ang-(1-7) in vivo is very short 9 and a large dose of Ang-(1-7) may cause adverse effects, 10 the dose-response relationship between Ang-(1-7) and early atherosclerotic lesions needs to be clarified. Second, it is unclear whether Ang-(1-7) is capable of inhibiting early atherosclerotic lesion formation and stabilizing mature atherosclerotic plaques.…”