Angiotensin II type 2 receptor gene transfer elicits cardioprotective effects in an angiotensin II infusion rat model of hypertension.
The role of the angiotensin II type 2 receptor (AT2R) in cardiovascular physiology remains elusive. We have developed an in vivo lentiviral vector-mediated gene transfer system to study the physiological functions of the AT2R. Our objectives in this study were to determine whether the AT2R influences cardiac hypertrophy and myocardial and perivascular fibrosis in a nongenetic rat model of hypertension. Lentiviral vector containing the AT2R or saline was injected intracardially in 5-day-old Sprague-Dawley rats. This resulted in a persistent overexpression of the AT2R in cardiac tissues. At 15 wk of age, animals were infused with either 200 ng x kg(-1) x min(-1) of angiotensin II or saline by implantation of a 4-wk osmotic minipump. This resulted in an increase in blood pressure (BP) that reached maximal by 2 wk of treatment and was associated with a 123% increase in left ventricular wall thickness (LVWT) and a 129% increase in heart weight to body weight ratios (HW/BW). 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 LVWT, 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 BP. Thus our observations indicate that long-term expression of the AT2R in the heart attenuates cardiac hypertrophy and fibrosis in a nongenetic rat model of hypertension.
Falcón
Beverly L
BL
Department of Physiology and Functional Genomics, College of Medicine and the Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
Stewart
Jillian M
JM
Bourassa
Erick
E
Katovich
Michael J
MJ
Walter
Glenn
G
Speth
Robert C
RC
Sumners
Colin
C
Raizada
Mohan K
MK
D000804:Angiotensin II / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006973:Hypertension / Q000139:chemically induced* / Q000517:prevention & control; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000517:prevention & control; D015918:Infusion Pumps, Implantable; D016086:Lentivirus / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000008:administration & dosage / Q000235:genetics* / Q000502:physiology* / Q000627:therapeutic use
D057912:Angiotensin II Type 2 Receptor Blockers; D002316:Cardiotonic Agents; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II