Background Activation of the renin-angiotensin system and the subsequent generation of angiotensin(Ang)Ⅱis an important mediator of myocardial fibrosis,pathological hypertrophy and heart failure.Angiotensin-converting enzyme 2(ACE2) has recently been identified as AngⅡ-degrading enzyme capable of generating Ang(1 -7) and as a negative regulator of the renin-angiotensin system.We assessed the hypothesis that ACE2 mediates its anti-fibrotic and anti-hyper-trophic effects through the modulation of AngⅡsignaling. Methods We implanted mini-osmotic pumps with AngⅡ(1.5 mg·kg~(-1)·d~(-1)) for 14 days in male wildtype(WT) mice which were then treated with recombinant human ACE2(rhACE2;2 mg·kg~(-1),d i.p.) or placebo.Systolic blood pressure of mouse was measured using the tail cuff method with the IITC Blood Pressure Monitoring Systems.Results Chronic AngⅡinfusion resulted in a predicted pressor response(peak SBP:163±7 mm Hg,n=8,P<0.01),treatment with rhACE2 reduced the pressor response(139±4 mm Hg;n=6,P<0.05)and reduced the hypertrophic response based on left ventricular mass and expressions of atrial natriuretic factor,brain natriuretic peptide andα-skeletal actin(P<0.05,respectively).Interestingly,echocardiographic assessment including tissue Doppler measurement revealed attenuated ventricular hypertrophy and improvement in diastolic dysfunction in AngⅡ-treated mice injected with rhACE2.Trichrome and picrosirius red staining showed a marked increase in myocardial fibrosis in response to AngⅡwhich was suppressed by rhACE2(collagen volume fraction; 7.3%±1.3%vs.4.1%±1.1%;n=6～7,P<0.05) with reduced expression of collagenⅠandⅢ,fibronectin and transforming growth factor-P in response to rhACE2.In male ACE2 knockout mice(Ace2-/y),AngⅡinfusion resulted in greater pressor response(186±8 mm Hg;re=8,P<0.01) and worsening diastolic dysfunction compared to WT mice infused with AngⅡ.Conclusions In the setting of elevated AngⅡ,loss of ACE2 increases AngⅡ-induced hypertension and diastolic dysfunction. In contrast,recombinant human ACE2 prevents AngⅡ-mediated hypertension,myocardial hypertrophy and fibrosis.We conclude that ACE2 plays a pivotal role in the prevention of hypertension,myocardial hypertrophy and fibrosis acting as a protective mechanism in the heart to limit the pathological effects of an activated systemic and/or local RAS and ACE2 represents a novel therapeutic strategy for cardiovascular disorders. Background Activation of the renin-angiotensin system and the subsequent generation of angiotensin (Ang) II is an important mediator of myocardial fibrosis, pathological hypertrophy and heart failure. Angiotensin-converting enzyme 2 (ACE2) has been identified as Ang II-degrading enzyme capable of generating Ang (1-7) and as a negative regulator of the renin-angiotensin system. We assessed the hypothesis that ACE2 mediates its anti-fibrotic and anti-hyper-trophic effects through the modulation of AngII signaling. Methods We implanted mini-osmotic pumps with AngⅡ (1.5 mg · kg -1 · d -1) for 14 days in male wildtype (WT) mice which were then treated with recombinant human ACE2 (rhACE2; 2 mg · kg -1) , d ip) or placebo. Systolic blood pressure of mouse was measured using the tail cuff method with the IITC Blood Pressure Monitoring Systems. Results Chronic Ang II infusion resulted in a predicted pressor response (peak SBP: 163 ± 7 mm Hg, n = 8, P <0.01), treatment with rhACE2 reduced the pressor res ponse (139 ± 4 mm Hg; n = 6, P <0.05) and reduced the hypertrophic response based on left ventricular mass and expressions of atrial natriuretic factor, brain natriuretic peptide and α-skeletal actin echocardiographic assessment including tissue Doppler measurement demonstrated attenuated ventricular hypertrophy and improvement in diastolic dysfunction in Ang II-treated mice injected with rhACE2.Trichrome and picrosirius red staining showed a marked increase in myocardial fibrosis in response to AngⅡwhich was suppressed by rhACE2 (collagen volume fraction; 7.3 % ± 1.3% vs.4.1% ± 1.1%; n = 6-7, P <0.05) with reduced expression of collagenⅠandⅢ, fibronectin and transforming growth factor-P in response to rhACE2.In male ACE2 knockout mice ), AngⅡinfusion resulted in greater pressor response (186 ± 8 mm Hg; re = 8, P <0.01) and worsening diastolic dysfunction compared to WT mice infused with AngⅡ.Conclusions In the setting of elevated AngⅡ, loss of ACE2 increases Ang Ⅱ-induced hypertension and diastoliIn contrast, recombinant human ACE2 prevents AngII-mediated hypertension, myocardial hypertrophy and fibrosis. We conclude that ACE2 plays a pivotal role in the prevention of hypertension, myocardial hypertrophy and fibrosis acting as a protective mechanism in the heart to limit the pathological effects of an activated systemic and / or local RAS and ACE2 represent a novel therapeutic strategy for cardiovascular disorders.