Effect of angiotensin-converting enzyme inhibition on protein kinase C and SR proteins in heart failure

Abstract

We tested the hypothesis that activation of protein kinase C (PKC) isoforms in pressure-overload heart failure was prevented by angiotensin-converting enzyme (ACE) inhibition, resulting in normalization of cardiac sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA) 2a and phospholamban protein levels and improvement in intracellular Ca2+ handling. Aortic-banded and control guinea pigs were given ramipril (5 mg ⋅ kg−1 ⋅ day−1) or placebo for 8 wk. Ramipril-treated banded animals had lower left ventricular (LV) and lung weight, improved survival, increased isovolumic LV mechanics, and improved cardiomyocyte Ca2+ transients compared with placebo-treated banded animals. This was associated with maintenance of SERCA2a and phospholamban protein expression. Translocation of PKC-α and -ε was increased in placebo-treated banded guinea pigs compared with controls and was attenuated significantly by treatment with ramipril. We conclude that ACE inhibition attenuates PKC translocation and prevents downregulation of Ca2+ cycling protein expression in pressure-overload hypertrophy. This represents a mechanism for the beneficial effects of this therapy on LV function and survival in heart failure.

Adenovirus-Mediated Overexpression of Diacylglycerol Kinase-ζ Inhibits Endothelin-1–Induced Cardiomyocyte Hypertrophy

“…9,10,24 Equal amounts of membranous and cytosolic protein were subjected to electrophoresis, and the subcellular localization of PKC isoforms was examined by quantitative immunoblotting with isoform-specific antibodies as reported previously. 9,10,24 Membrane/cytosol ratios of immunoreactivity were used as indices for the extent of translocation of PKC isoforms. 9,10,24…”

“…4 In animal models of cardiac hypertrophy and heart failure by pressure overload, translocation and activation of PKC-␣ and PKC-⑀ isoforms are observed. 9,24 We have demonstrated that transgenic overexpression of a constitutively active mutant of the PKC-⑀ isoform in the mouse heart results in concentric cardiac hypertrophy. 11 Conversely, overexpression of PKC-␤2 in transgenic mouse heart causes a dilated cardiomyopathy phenotype.…”

“…6 Previous studies in human heart failure and animal models of heart failure that included genetically engineered mice clearly demonstrated that activation of PKC plays a pivotal role in the development of cardiac hypertrophy and heart failure. [7][8][9][10][11] DAG kinase (DGK) is an enzyme that is responsible for controlling the cellular levels of DAG by converting it to phosphatidic acid 12 and thus is thought to act as an endoge-nous regulator of PKC activity. To date, 9 mammalian DGK isoforms, which differ in tissue expression and structural domains, have been identified.…”

Mineralocorticoid and Angiotensin Receptor Antagonism During Hyperaldosteronemia

“…ACEI and Ang II receptor antagonists have been reported to prevent translocation of ⑀PKC in the heart, 29,30 and in a recent study from our laboratory, ⑀PKC was shown to mediate Ang II-mediated inhibition of pump activity. 31 Aldosterone-induced activation of PKC in noncardiac tissue has been reported by several studies, 32,33 and a similar response in the heart might contribute in part to the aldosterone-induced inhibition of pump function observed in the present study.…”

ACE inhibition in aortic stenosis: dangerous medicine or golden opportunity?

“…20,31 Such a change has been demonstrated in aortic-banded guinea pigs, as they develop pressure-overloaded heart failure, and the decrease in Ca 2+ -ATPase expression can be attenuated significantly by 8 weeks of treatment with an ACE inhibitor. 32 Neuroendocrine activity has also been implicated, in particular local production of angiotensin II, in the apoptosis hypothesis for explaining progressive alterations in chamber contractility. Myocyte apoptosis has been demonstrated to contribute in rats and mice to the transition from hypertrophy to early heart failure.…”