Recently discovered, angiotensin-converting enzyme-2 (ACE2) is an important therapeutic target in the control of cardiovascular diseases as a result of its proposed central role in the control of angiotensin peptides. Thus our objective in the present study was to determine whether ACE2 gene transfer could decrease high blood pressure (BP) and would improve cardiac dysfunctions induced by hypertension in the spontaneously hypertensive rat (SHR) model. Five-day-old SHR and normotensive WKY rats received a single intracardiac bolus injection of lentiviral vector containing either murine ACE2 (ACE2) or control enhanced green fluorescent protein (EGFP) genes. Systolic BP, cardiac functions, and perivascular fibrosis were evaluated 4 mo after ACE2 gene transduction. ACE2 gene transfer resulted in a significant attenuation of high BP in the SHR (149 +/- 2 mmHg in lenti-ACE2 vs. 180 +/- 9 mmHg in lenti-EGFP, P < 0.01). In contrast, no significant effect of lenti-ACE2 on BP of WKY rats was observed. Lenti-ACE2-treated SHR showed an 18% reduction in left ventricular wall thickness (1.52 +/- 0.04 vs. 1.86 +/- 0.04 mm in lenti-EGFP, P < 0.01). In addition, there was a 12% increase in left ventricular end diastolic and a 21% increase in end systolic diameters in lenti-ACE2-treated SHR. Finally, lenti-ACE2 treatment resulted in a significant attenuation of perivascular fibrosis in the SHR. In contrast, ACE2 gene transfer did not influence any of these parameters in WKY rats. These observations demonstrate that ACE2 overexpression exerts protective effects on high BP and cardiac pathophysiology induced by hypertension in the SHR.