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Obesity Is Associated With Impaired Ventricular Protein Kinase C-MAP Kinase Signaling and Altered ANP mRNA Expression in the Heart of Adult Zucker Rats
  1. Dominique Morabito,
  2. Michel B. Vallotton,
  3. Ursula Lang
  1. From the Division of Endocrinology and Diabetology, University Hospital, Geneva, Switzerland.
  1. Address correspondence to: Dr Ursula Lang, University Hospital, Division of Endocrinology and Diabetology, 24, Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail LANGU{at}cmu.unige.ch
  2. This study was supported by grants no. 31-42295.94 and 31-52935.97 from the Swiss National Science Foundation (CP 8232, CH-3001 Bern, Switzerland).

Abstract

Background In the obesity model of the Zucker rat, myocardial protein kinase C (PKC) activation by phorbol ester is impaired. The influence of obesity 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 induction of ANP mRNA.

Methods Isolated hearts obtained from 17-week-old lean and obese Zucker rats were perfused with 200 nM phorbol 12-myristate 13-acetate (PMA) at different 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 PKCα from the cytosol to the membranes within 10 minutes in lean rats, whereas it had a much weaker effect in obese rats. Moreover, PMA induced a significant activation of PKCΔ in lean but not in obese rat hearts. After PKC activation, increases in phosphorylation levels of myocardial p38 and p42 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 transduction cascade PKC-MAPK-ANP mRNA seems to be markedly impaired. It can be speculated that this abnormal cardiac cell signaling in obese rats reflects an early phase in the cardiac pathogenesis accompanying obesity.

Keywords
  • isolated heart perfusion
  • phorbol 12-myristate 13-acetate
  • PKCα
  • Δ
  • ε
  • ζ
  • p38-MAPK
  • p42/44- MAPK

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