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1 Department of Physiology and Functional Genomics, University of Florida, College of Medicine, Gainesville, Florida, USA
2 Pharmacology, School of Pharmacy, University of Mississippi, University, Mississippi, USA
3 Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA
* To whom correspondence should be addressed. E-mail: mraizada{at}phys.med.ufl.edu.
The role of the angiotensin II type 2 receptor (AT2R) in cardiovascular physiology remains elusive. We have developed an in vivo lentiviral vectormediated gene transfer system to study the physiological functions of the AT2R. Our objectives in this study were to determine if the AT2R influences cardiac hypertrophy and myocardial and perivascular fibrosis in a non-genetic rat model of hypertension. Lenti-viral vector containing the AT2R or saline was injected intracardially in five-day old Sprague Dawley rats. This resulted in a persistent overexpression of the AT2R in cardiac tissues. At 15 weeks of age, animals were infused with either 200ng/kg/min of angiotensin II or saline by implantation of a 4-week osmotic minipump. This resulted in an increase in blood pressure that reached maximal by 2 weeks of treatment, and was associated with a 123% increase in left ventricular wall thickness and a 129% increase in heart weight to body weight ratios. In addition, the increase in cardiac hypertrophy was associated with a 300% and 158% increase in myocardial and perivascular fibrosis, respectively. Cardiac transduction of the AT2R resulted in an 85% attenuation of left ventricular wall thickness, 91% attenuation of HW/BW and a 43% decrease in myocardial fibrosis induced by angiotensin-infusion. These improvements in cardiac pathology were observed in the absence of attenuation of high blood pressure. Thus, our observations indicate that long-term expression of the AT2R in the heart attenuates cardiac hypertrophy and fibrosis in a non-genetic rat model of hypertension.
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