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 implicated in the development of cardiac hypertrophy through the activation of specific target genes. However, the relative importance of these putative hypertrophic stimuli has not been established in vivo. We used an isolated isovolumic heart preparation in which coronary perfusion pressure (CPP), left ventricular end-diastolic pressure, and pharmacological therapy can be independently manipulated to study this relationship. High CPP (140 cmH2O), which increased coronary flow (8.99 vs. 17.6 ml/min) and left ventricular systolic pressure (50 vs. 91 mmHg), increased steady state c-fos mRNA expression 2.3-fold (all P < 0.01 vs. low CPP). In contrast, increased left ventricular end-diastolic pressure (25 mmHg) and/or infusion of angiotensin II in the absence of increased CPP was not associated with an increase in c-fos mRNA expression. The change in c-fos gene expression seen with increased CPP was largely reversed by treatment with an angiotensin type 1 (AT1) receptor blocker. Hearts perfused at high CPP demonstrated increased translocation/activation of protein kinase C-epsilon relative to controls. None of the hearts studied were ischemic during perfusion. Thus, in the perfused adult rat heart, dynamic, but not static, stretch activates the early response gene, c-fos, and may involve the endogenous reninangiotensin system and protein kinase C.
Kang
P M
PM
Division of Cardiology, Albert Einstein College of Medicinea Montefiore Medical Center, Bronx, New York 10467, USA.
Nakouzi
A
A
Simpson
T
T
Scheuer
J
J
Buttrick
P M
PM
D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001696:Biomechanical Phenomena; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000502:physiology*
D057911:Angiotensin Receptor Antagonists; D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D000804:Angiotensin II; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon