Mechanisms of Myocardial Remodeling: Ramiprilat Blocks the Expressional Upregulation of Protein Kinase C-ε in the Surviving Myocardium Early After Infarction

Abstract

Inhibition of angiotensin-converting enzyme (ACEI) after myocardial infarction reduces remodeling of the surviving myocardium. The cellular signaling mechanisms contributing to remodeling are not fully elucidated. Goal of the current study was to test whether protein kinase C (PKC) is regulated in the surviving myocardium shortly after infarction and whether this regulation is influenced by ACEI. Rats were subjected to anterior wall myocardial infarction in vivo or sham operation. After 15-45 min, mRNA levels and protein expression of the major cardiac PKC isoforms were measured in the ischemic and the remote myocardium. The influence of ACEI on PKC was tested by pretreating the rats with ramiprilat. In the ischemic region of the myocardium, a significant increase of the mRNA for PKC-delta and PKC-epsilon was observed in close correlation with increased isoform protein expression. In the surviving, remote myocardium, however, only PKC-epsilon expression was significantly augmented both at the mRNA level (158%) and at the protein level (149%). PKC-delta and PKC-alpha were unchanged. Treatment with ramiprilat could abolish this isoform-specific PKC regulation in both areas. These data characterize for the first time an isoform-specific transcriptional regulation process of PKC in the surviving myocardium after infarction. This induction of PKC-epsilon can be prevented by ACEI. It is speculated that PKC-epsilon plays a role in the signal transduction of early remodeling after infarction.

Antioxidant and Nitric Oxide-Sparing Actions of Dihydropyridines and ACE Inhibitors Differ in Human Endothelial Cells

“…Thus, inhibition of PKC-mediated NADPH oxidase activation or eNOS modulation might contribute to the observed antioxidant actions of DHP in the present study. Interestingly, the ACE inhibitor, ramiprilat was also able to suppress superoxide formation induced by PMA, a fi nding that is in agreement with other published results [46,47] .…”

Protein kinase C, an elusive therapeutic target?

“…However, failed human hearts show at most a small increase in αPKC activation. In contrast, a more than 2X increase in βPKC activation 33,34,240,241 and in two models of HF in rats (βIIPKC ) 109 . Conflicting data were obtained on the role of PKCβ in HF using transgenic mice 205–209 .…”

“…Increased activation of select PKC isozymes have been observed in cancer 3,31 , diabetes 32 , ischemic heart disease 33,34 , acute and chronic heart disease 35 , heart failure 34,36 , lung 37 and kidney 38,39 diseases, a number of dermatological diseases including psoriasis 12 , in autoimmune diseases 6,40 and in a number of neurological diseases, including stroke 41 , Parkinson’s disease 7,8 , dementia 42 , Alzheimer’s disease 9,43 , pain 44 and even in psychiatric diseases, including bipolar disease 10 . Initially, the role of PKC in various illnesses was implicated because abnormal activation or levels of a particular isozyme in the disease state was noted.…”

Polyphenol compounds and PKC signaling

“…Role of different PKC isoforms in various types of cancer has been reviewed by Griner and Kazanietz [57]. PKCs are also implicated in cardiovascular diseases like ischemic heart disease [58, 59], acute and chronic heart disease [60], heart failure [61], stroke [62], lung [63] and kidney complications [64], diabetes [65], various dermatological conditions including psoriasis [66], neurological disease states like bipolar disorders [67], Parkinson's disease [68, 69] dementia [70], Alzheimer's disease [71, 72], and pain [73]. One of the major goals of studying PKC isozymes is to develop potent and selective ligands to regulate PKC signaling in these disease states and the significance of PKC as a therapeutic target has been elegantly reviewed by Mochley-Rosen et al [74].…”