What is the clinical evidence from this study?

Study design: Other. Intervention: Angiotensin II vs. Control (serum-free media). Primary outcome: ACE2 mRNA and activity (p=<0.01).

October 11, 2008Open Access

Regulation of ACE2 in cardiac myocytes and fibroblasts

Q: What are the key findings of this study?

Angiotensin II significantly reduced ACE2 activity and downregulated ACE2 mRNA in cardiac myocytes, an effect blocked by the ARB losartan.

Key Result

Angiotensin II significantly reduced ACE2 activity and downregulated ACE2 mRNA in cardiac myocytes, an effect blocked by the ARB losartan.

Structured PICO

Population

In vitro study using cardiac myocytes and fibroblasts isolated from the ventricles of neonatal (1- to 2-day old) Sprague-Dawley rats.

Intervention

In vitro treatment with ANG II (100 nM) or ET-1 (10 nM) in the presence or absence of losartan, MEK inhibitors (PD-98059, U-0126), ANG-(1-7), or ANP

Comparator

Untreated control cells or cells treated with agonist alone

Outcome

ACE2 mRNA expression and ACE2 catalytic activitysurrogate

ANG II and ET-1 downregulate ACE2 expression in cardiac myocytes via ERK1/ERK2 signaling, an effect opposed by ANG-(1-7) and ANP, suggesting a complex regulatory network for ACE2 in cardiac hypertrophy.

Main Result

p-value: p=<0.01

Abstract

Angiotensin-converting enzyme 2 (ACE2) preferentially forms angiotensin-(1-7) ANG-(1-7) from ANG II. We showed that cardiac ACE2 is elevated following treatment of coronary artery-ligated rats with AT1 receptor blockers (ARBs). Cardiac myocytes and fibroblasts were isolated from neonatal rats to determine the molecular mechanisms for the ACE2 upregulation by ARB treatment. ANG II significantly reduced ACE2 activity and downregulated ACE2 mRNA in cardiac myocytes, effects blocked by the ARB losartan, indicating that ANG II regulates ACE2. ANG II also reduced ACE2 mRNA in cardiac fibroblasts; however, no enzyme activity was detected, reflecting the limited expression of ACE2 in these cells. Endothelin-1 (ET-1) also significantly reduced myocyte ACE2 mRNA. The reduction in ACE2 mRNA by ANG II or ET-1 was blocked by inhibitors of mitogen-activated protein kinase kinase 1, suggesting that ANG II or ET-1 activates extracellular signal-regulated kinase (ERK) 1/ERK2 to reduce ACE2. Although ACE2 mRNA was not affected by ANG-(1-7), both the ANG II- and ET-1-mediated reductions in ACE2 mRNA were blocked by the heptapeptide. The ANG-(1-7) modulatory effect was prevented by the ANG-(1-7) receptor antagonist D-Ala7-ANG-(1-7), indicating that the ANG-(1-7) response was mediated by a specific AT(1-7) receptor. Myocyte treatment with atrial natriuretic peptide (ANP) also reversed the ACE2 mRNA downregulation by ANG II or ET-1, whereas treatment with ANP alone was ineffective. These results indicate that multiple hypertrophic and anti-hypertropic peptides regulate ACE2 production in myocytes, suggesting that ACE2 expression in the heart is dependent upon the compliment and concentration of regulatory molecules.

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