ROLE OF ENDOGENOUS RENIN-ANGIOTENSIN SYSTEM IN C-FOS ACTIVATION AND PKC-EPSILON TRANSLOCATION IN ADULT-RAT HEARTS

Myocardial stretch and the renin-angiotensin system have been implicat ed in the development of cardiac hypertrophy through the activation of specific target genes. However, the relative importance of these puta tive hypertrophic stimuli has not been established in vivo. We used an isolated isovolumic heart preparation in which coronary perfusion pre ssure (CPP), left ventricular end-diastolic pressure, and pharmacologi cal therapy can be independently manipulated to study this relationshi p. High CPP (140 cmH(2)O), which increased coronary flow (8.99 vs. 17. 6 ml/min) and left ventricular systolic pressure (50 vs. 91 mmHg), inc reased steady state c-fos mRNA expression 2.3-fold (all P < 0.01 vs. l ow CPP). In contrast, increased left ventricular end-diastolic pressur e (25 mmHg) and/or infusion of angiotensin II in the absence of increa sed CPP was not associated with an increase in c-fos mRNA expression. The change in c-fos gene expression seen with increased CPP was largel y reversed by treatment with an angiotensin type 1 (AT(1)) receptor bl ocker. Hearts perfused at high CPP demonstrated increased translocatio n/activation of protein kinase C-epsilon relative to controls. None of the hearts studied were ischemic during perfusion. Thus, in the perfu sed adult rat heart, dynamic, but not static, stretch activates the ea rly response gene, c-fos, and may involve the endogenous renin-angiote nsin system and protein kinase C.