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Pathological cardiac hypertrophy is regarded as a critical intermediate step toward the development of heart failure. Many signal transduction cascades are demonstrated to dictate the induction and progression of pathological hypertrophy; however, our understanding in regulatory mechanisms responsible for the suppression of hypertrophy remains limited. In this study, we showed that exacerbated hypertrophy induced by pressure overload in cardiac-deleted Pak1 mice was attributable to a failure to upregulate the antihypertrophic E3 ligase, Fbxo32, responsible for targeting proteins for the ubiquitin-degradation pathway. Under pressure overload, cardiac overexpression of constitutively active Pak1 mice manifested strong resilience against pathological hypertrophic remodeling. Mechanistic studies demonstrated that subsequent to Pak1 activation, the binding of Smad3 on a critical singular AGAC(-286)-binding site on the FBXO32 promoter was crucial for its transcriptional regulation. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling and improved cardiac performance in cardiac-deficient Pak1 mice under pressure overload. Our findings discover Smad3 and Fbxo32 as novel downstream components of the Pak1-dependent signaling pathway for the suppression of hypertrophy. This discovery opens a new venue for opportunities to identify novel targets for the management of cardiac hypertrophy.

Original publication

DOI

10.1161/HYPERTENSIONAHA.115.06068

Type

Journal

Hypertension

Publication Date

12/2015

Volume

66

Pages

1176 - 1183

Keywords

Fbxo32 protein, mouse, Smad3 protein, hypertrophy, p21-activated kinases, ubiquitin, Animals, Animals, Newborn, Aorta, Berberine, Cardiomegaly, Cells, Cultured, Constriction, Pathologic, Immunoblotting, Male, Mice, Knockout, Mice, Transgenic, Muscle Proteins, Myocytes, Cardiac, Phosphorylation, Rats, Reverse Transcriptase Polymerase Chain Reaction, SKP Cullin F-Box Protein Ligases, Signal Transduction, Smad3 Protein, Transcriptional Activation, p21-Activated Kinases