Soluble Angiotensin-Converting Enzyme 2 in Human Heart Failure: Relation With Myocardial Function and Clinical Outcomes

Epelman, Slava; Shrestha, Kevin; Troughton, Richard W.; Francis, Gary S.; Sen, Subha; Klein, Allan L.; Tang, W.H. Wilson

doi:10.1016/j.cardfail.2009.01.014

Cited by 190 publications

(218 citation statements)

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“…[1][2][3]7 ACE2 has emerged as an important determinant of heart disease, 16,28 and increasing serum ACE2 activity correlates with worsening LV function and poor clinical outcomes in patients with heart failure. 29 The present data show that in a setting of elevated Ang II levels, absence of ACE2 results in greater pathological ventricular hypertrophy and fibrosis, which results in worsening diastolic dysfunction. In contrast, treatment with rhACE2 prevented Ang II-induced hypertrophy and myocardial fibrosis.…”

Section: Discussionmentioning

confidence: 83%

Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction

et al. 2010

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Background-Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabolizing several peptide substrates. We hypothesized that ACE2 is a negative regulator of angiotensin II (Ang II)-mediated signaling and its adverse effects on the cardiovascular system. Methods and Results-Ang II infusion (1.5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) for 14 days resulted in worsening cardiac fibrosis and pathological hypertrophy in ACE2 knockout (Ace2 Ϫ/y ) mice compared with wild-type (WT) mice. Daily treatment of Ang II-infused wild-type mice with recombinant human ACE2 (rhACE2; 2 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 IP) blunted the hypertrophic response and expression of hypertrophy markers and reduced Ang II-induced superoxide production. Ang II-mediated myocardial fibrosis and expression of procollagen type I␣1, procollagen type III␣1, transforming growth factor-␤1, and fibronectin were also suppressed by rhACE2. Ang II-induced diastolic dysfunction was inhibited by rhACE2 in association with reduced plasma and myocardial Ang II and increased plasma Ang 1-7 levels. rhACE2 treatment inhibited Ang II-mediated activation of protein kinase C-␣ and protein kinase C-␤1 protein levels and phosphorylation of the extracellular signal-regulated 1/2, Janus kinase 2, and signal transducer and activator of transcription 3 signaling pathways in wild-type mice. A subpressor dose of Ang II (0.15 mg ⅐ kg) resulted in a milder phenotype that was strikingly attenuated by rhACE2 (2 mg ⅐ kgIn adult ventricular cardiomyocytes and cardiofibroblasts, Ang II-mediated superoxide generation, collagen production, and extracellular signal-regulated 1/2 signaling were inhibited by rhACE2 in an Ang 1-7-dependent manner. Importantly, rhACE2 partially prevented the development of dilated cardiomyopathy in pressure-overloaded wild-type mice. Conclusions-Elevated Ang II induced hypertension, myocardial hypertrophy, fibrosis, and diastolic dysfunction, which were exacerbated by ACE2 deficiency, whereas rhACE2 attenuated Ang II-and pressure-overload-induced adverse myocardial remodeling. Hence, ACE2 is an important negative regulator of Ang II-induced heart disease and suppresses adverse myocardial remodeling. (Circulation. 2010;122:717-728.)Key Words: angiotensin Ⅲ signal transduction Ⅲ hypertrophy Ⅲ remodeling Ⅲ diastole A ctivation of the renin-angiotensin system (RAS) and the subsequent generation of angiotensin (Ang) II are important mediators of myocardial fibrosis, pathological hypertrophy, and heart failure. 1-3 Pathological hypertrophy and increased myocardial interstitial fibrosis contribute to increased ventricular wall stiffness, thereby impairing cardiac diastolic function, and represent an important risk factor for heart failure in experimental models and patients. 4 -6 Drugs that target Ang II and the Ang II type 1 receptor (AT 1 ) are widely used for the treatment of cardiovascular diseases such as hypertension, myocardial infarction, and heart failure. 7 Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabo...

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Section: Discussionmentioning

confidence: 83%

Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction

et al. 2010

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“…In addition, the catalytic domains of the two enzymes share a single anion binding site mediating the anion-dependent activation observed in both ACE and ACE2 [22]. Although ACE2 is a plasma membrane-bound ectoenzyme, a soluble active form of this enzyme is also found in plasma and urine [23]. Tumor necrosis factor alpha converting enzyme (TACE/ADAM17) is the sheddase responsible for the ectodomain cleavage and shedding of ACE2 [24].…”

Section: Biochemical Aspects Of Ace2mentioning

confidence: 99%

“…In the human population, genetic variability in the ACE2 gene correlates with susceptibility to cardiovascular disease. In human heart failure, plasma ACE2 activity is increased and correlates with adverse clinical outcomes [23,40]. The expression of ACE2 shows a dramatic decrease with aging independent of gender [41].…”

Section: Biochemical Aspects Of Ace2mentioning

confidence: 99%

Role of ACE2 in diastolic and systolic heart failure

et al. 2011

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A novel angiotensin-converting enzyme (ACE) homolog, named ACE2, is a monocarboxypeptidase which metabolizes several peptides. ACE2 degrades Angiotensin (Ang) II, a peptide with vasoconstrictive/proliferative effects, to generate Ang-(1-7), which acting through its receptor Mas exerts vasodilatory/anti-proliferative actions. In addition, as ACE2 is a multifunctional enzyme and its actions on other vasoactive peptides can also contribute to its vasoactive effects including the apelin-13 and apelin-17 peptides. The discovery of ACE2 corroborates the establishment of two counter-regulatory arms within the renin-angiotensin system. The first one is formed by the classical pathway involving the ACE-Ang II-AT(1) receptor axis and the second arm is constituted by the ACE2-Ang 1-7/Mas receptor axis. Loss of ACE2 enhances the adverse pathological remodeling susceptibility to pressure-overload and myocardial infarction. ACE2 is also a negative regulator of Ang II-induced myocardial hypertrophy, fibrosis, and diastolic dysfunction. The ACE2-Ang 1-7/Mas axis may represent new possibilities for developing novel therapeutic strategies for the treatment of hypertension and cardiovascular diseases. In this review, we will summarize the biochemical and pathophysiological aspects of ACE2 with a focus on its role in diastolic and systolic heart failure.

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“…ACE2 is a membrane-bound monocarboxypeptidase (120 kDa) that converts ANG II directly to ANG-(1-7). Circulating levels of ACE2 are typically quite low particularly compared with ACE; however, serum ACE2 activity is elevated in diabetes, heart failure, and hypertension (41,136,148). ACE2 has a potentially significant role in the RAS pathway as a single catalytic step degrades ANG II but activates the ANG-(1-7) axis ( Fig.…”

Section: Ras Protein Componentsmentioning

confidence: 99%

Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

Chappell

2016

American Journal of Physiology-Heart and Circulatory Physiology

231

256

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Soluble Angiotensin-Converting Enzyme 2 in Human Heart Failure: Relation With Myocardial Function and Clinical Outcomes

Cited by 190 publications

References 30 publications

Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction

Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction

Role of ACE2 in diastolic and systolic heart failure

Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

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