P62A novel CaMKII/ERK interaction in the heart sustains cardiac hypertrophy in spontaneously hypertensive rats

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Abstract

The cardiac hypertrophy is an adaptive response to increased cardiac output that occurs in various cardiovascular diseases. The molecular mechanisms underlying it involve, among others, abnormal intracellular Ca + + dynamics. Ca + + /Calmodulin protein kinase II (CaMKII) activation has a role in the hypertrophic signaling transduction pathways. However, the mechanism by which CaMKII integrates with other pathways to develope cardiac hypertrophy is incompletely understood. We already showed that phenylephrine (PE) induced VSMC (vascular smooth muscle cell) proliferation results in CaMKII and ERK complex formation which promotes phosphorylation and nuclear localization of both proteins. We hypothesize that CaMKII, in association with ERK, promotes nuclear localization in hypertrophic cardiomyocytes. In H9c2 cardiomyoblasts PE induces both ERK and CaMKII activation, that were been affected by non-selective CaMKs inhibition with KN93 or by selective CaMKII inhibitor AntCaNtide, as well as MEK/ERK inhibitor UO126. Co-immunoprecipitating studies demonstrated that PE induces CaMKII/ERK interaction, which was prevented by pre-treatment with KN93, ANtCaNTide or UO126. Next, we tracked the intracellular localization of ERK and CaMKII. PE induces a time-dependent accumulation of both ERK and CaMKII into the nucleus. AnTCaNtide and UO126 pretreatment prevented not only ERK but also CaMKII nuclear localization, supporting the hypothesis that ERK activation is required for CaMKII nuclear localization. In order to determine the role of CaMKII in in vivo cardiac hypertrophy, Spontaneously Hypertensive Rats (SHR) were subjected to intracardiac injection of AnTCaNtide (ANTS,50mcg/kg, n = 8). Sham group of SHR (SS,n = 8) were subjected to intracardiac injection of saline. After 3 and 7 days from the treatment, we performed an ultrasound (US,VeVo-Visualsonics) cardiac evaluation and an invasive (Millar) arterial BP measurement in the rats. Mean arterial pressure and body weight were similar between SS and ANTS, but we observed in ANTS a significant reduction of cardiac size (ANTS vs SS:Heart weight/body ratio 3.961 ± 0.02586 vs 4.177 ± 0.02583,p < 0.05), of US left ventricular mass (ANTS vs SS:785.15 ± 47.4g vs 963.92 ± 51.6g,p < 0.05) and of US thickness of interventricular septum (ANTS vs SS:1.821 ± 0. 01063mm vs 1.918 ± 0.01797mm,p < 0.05). Finally in ANTS we observed a significant reduction of CaMKII and ERK phosphorylation levels. These results indicate that CaMKII promotes ERK activation in hypertrophic hearts and functional significance of CaMKII-ERK interaction offers a novel therapeutic approach to limit pathological cardiac hypertrophy.

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