Herpud1 negatively regulates pathological cardiac hypertrophy by inducing IP3 receptor degradation
Cardiac hypertrophy is an adaptive response triggered by pathological stimuli. Regulation of the synthesis and the degradation of the Ca2+ channel inositol 1,4,5-trisphosphate receptor (IP3R) affects progression to cardiac hypertrophy. Herpud1, a component of the endoplasmic reticulum-associated degradation (ERAD) complex, participates in IP3R1 degradation and Ca2+ signaling, but the cardiac function of Herpud1 remains unknown. We hypothesize that Herpud1 acts as a negative regulator of cardiac hypertrophy by regulating IP3R protein levels. Our results show that Herpud1-knockout mice exhibit cardiac hypertrophy and dysfunction and that decreased Herpud1 protein levels lead to elevated levels of hypertrophic markers in cultured rat cardiomyocytes. In addition, IP3R levels were elevated both in Herpud1-knockout mice and Herpud1 siRNA-treated rat cardiomyocytes. The latter treatment also led to elevated cytosolic and nuclear Ca2+ levels. In summary, the absence of Herpud1 generates a pathological hypertrophic phenotype by regulating IP3R protein levels. Herpud1 is a novel negative regulator of pathological cardiac hypertrophy.
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT, Chile) Fondo de Financiamiento de Centros de Investigacion en Areas Prioritarias (FONDAP) 15130011 Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) 1161156 Japan Society for the Promotion of Science
Artículo de publicación ISI
Quote ItemScientific Reports 7: 13402
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