Obesity is associated with impaired ventricular protein kinase C-MAP kinase signaling and altered ANP mRNA expression in the heart of adult Zucker rats

Background: In the obesity model of the Zucker rat, myocardial protein kina se C (PKC) activation by phorbol ester is impaired. The influence of obesit y on myocardial cell signaling was investigated by studying the activation of PKC isozymes and MAP kinases (MAPK) p38 and p42/44 as well as the induct ion of ANP mRNA. Methods: Isolated hearts obtained from 17-week-old lean and obese Zucker ra ts were perfused with 200 nM phorbol 12-myristate 13-acetate (PMA) at diffe rent time periods, Immunodetectable PKC isozymes, phosphorylated-MAPK, and ANP mRNA were determined by Western and Northern blots, respectively. Results: PMA promoted a marked transient translocation of ventricular PKC a lpha from the cytosol to the membranes within 10 minutes in lean rats, wher eas it had a much weaker effect in obese rats. Moreover, PMA induced a sign ificant activation of PKC delta in lean but not in obese rat hearts. After PKC activation, increases in phosphorylation levels of myocardial p38 and p 42 MAPK were approximately 3-fold higher in lean rats than in obese animals . Concerning the induction of ANP, PMA transiently tripled ANP mRNA within 60 minutes in lean but not in obese rats, Conclusions:In the genetically obese Zucker rat, the myocardial signal tran sduction cascade PKC-MAPK-ANP mRNA seems to be markedly impaired, It can be speculated that this abnormal cardiac cell signaling in obese rats reflect s an early phase in the cardiac pathogenesis accompanying obesity.