Abstract
BackgroundAngiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1–7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. Irbesartan has the dual actions of angiotensin receptor blockade and peroxisome proliferator-activated receptor-γ (PPARγ) activation. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARγ signaling.Methods10-week-old ACE2 knockout (ACE2KO; Ace2-/y) mice received daily with irbesartan (50 mg/kg) or saline for 2 weeks. The wild-type mice (Ace2+/y) were used to the normal controls. We examined changes in myocardial ultrastructure, fibrosis-related genes and pathological signaling by real-time PCR gene array, Western blotting, Masson trichrome staining and transmission electron microscope analyses, respectively.ResultsCompared with the Ace2+/y mice, cardiac expression of PPARα and PPARγ were reduced in Ace2-/y mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), collagen I and collagen III. Moreover, ACE2 deficiency triggered cardiac hypertrophy, increased myocardial fibrosis and adverse ultrastructure injury in ACE2KO hearts with higher levels of atrial natriuretic factor (ANF) and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), without affecting cardiac systolic function. Intriguingly, treatment with irbesartan significantly reversed ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in Ace2-/y mice linked with enhancement of plasma Ang-(1–7) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGFβ1, CTGF, collagen I, collagen III and phosphorylated ERK1/2 were lower, and expression of PPARγ was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPARα, PPARδ, β-myosin heavy chain, TGFβ2 and fibronectin.ConclusionsWe conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPARγ signaling and suppression of the TGFβ−CTGF−ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPARγ represent potential candidates to prevent and treat myocardial injury and related cardiac disorders.
Highlights
Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin Angiotensin II (II) (Ang II) to generate Ang-(1–7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive
We conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the peroxisome proliferatoractivated receptor-γ (PPARγ) signaling and suppression of the transforming growth factor-β (TGFβ)−connective tissue growth factor (CTGF) −ERK signaling, resulting in attenuation of myocardial injury
Treatment with irbesartan attenuated ACE2 deficiencymediated myocardial fibrosis and ultrastructure injury in ACE2 knockout (ACE2KO) mice We firstly evaluated the effects of ACE2 deficiency on myocardial fibrosis and injury
Summary
Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1–7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARγ signaling. Through the actions of its main biological peptide, angiotensin (Ang) II, the renin-angiotensin system (RAS) has been implicated in myocardial remodeling and heart failure [1,2,3]. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of the RAS and has recently been implicated in pathological hypertrophy and heart failure [2,7,8]. The exact roles and mechanisms of the ACE2 involved in myocardial hypertrophy, fibrosis and cardiac injury are largely unknown
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