Abstract
Heat shock protein 90 (HSP90), one of the most abundant proteins in the cardiac cells is essential for cell survival. Previous studies have shown that angiotensin II induces cardiac cell hypertrophy. However, the role of HSP90 in the angiotensin II-induced cardiac hypertrophy is unclear. In this study, we showed that HSP90 regulated angiotensin II-induced hypertrophy via maintenance of the IκB kinase (IKK) complex stability in cardiac cells. An HSP90 inhibitor, geldanamycin (GA), significantly suppressed angiotensin II-induced [³H]leucine incorporation and atrial natriuretic factor expression in cardiac cells. GA also inhibited the NF-κB activation induced by angiotensin II. Importantly, treatment with GA caused a degradation of IKKα/β; on the other hand, a proteasome-specific inhibitor restored the level of IKKα/β. We also found that GA prevented HSP90-IKKs complex induced by angiotensin II in cardiac cells. The small interfering RNA (siRNA)-mediated knockdown of HSP90 expression significantly inhibited angiotensin II-induced cell hypertrophy and NF-κB activation. These results suggest that angiotensin II-induced cardiac hypertrophy requires HSP90 that regulates the stability and complex of IKK.
Highlights
Cardiac hypertrophy is an increase in the size of cardiac myocytes to generate greater muscle mass, usually driven by a larger workload for the heart (Heineke et al, 2006)
We investigated the role of Heat shock protein 90 (HSP90) on nuclear factor-κB (NF-κB) activation pathway in angiotensin II-induced cardiac cell hypertrophy
NF-κB plays an important role in cardiac hypertrophy induced by angiotensin II (Li et al, 2004; Freund et al, 2005)
Summary
Cardiac hypertrophy is an increase in the size of cardiac myocytes to generate greater muscle mass, usually driven by a larger workload for the heart (Heineke et al, 2006). Angiotensin II, a vasoactive octapeptide, is an important humoral factor responsible for cardiac hypertrophy (Kim and Iwao, 2000). Numerous studies have shown that angiotensin II induces nuclear factor-κB (NF-κB) activation in cultured cardiac cells (Brasier et al, 2000; Kim and Iwao, 2000) and reported that the activation of NF-κB is required for hypertrophic responses from primary rat neonatal ventricular cardiomyocytes (Purcell et al, 2001; Li et al, 2004). NF-κB is a ubiquitously expressed cytoplasmic transcription factor whose primary mode of regulation is through nuclear translocation. The most abundant form of NF-κB transcription factor is heterodimer of p65 and p50 in several family members (Pereira and Oakley, 2008). One of the best-known pathways of IκBα phosphorylation is activation of IκB kinase (IKK) complex, which is composed of IKKα/β and IKKγ, and these possess essential kinase activity to phosphorylate IκB (Luo et al, 2005)
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