Abstract
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.
Highlights
Pathological cardiac hypertrophy is a phenotypic alteration of the heart to compensate for loss of function after myocardial infarction or in association with chronic stress, as in hypertension[1,2,3]
The distribution of Herpud[1] in the adult heart in WT and KO mice as well as in Neonatal rat ventricular myocytes (NRVM) was studied by immunohistochemistry and immunocytochemistry (Supplementary Fig. 2), These results provide the first evidence of the presence and distribution of Herpud[1] in the mouse heart
Diverse proteins and cellular processes are involved in the genesis and progression of pathological cardiac hypertrophy
Summary
Pathological cardiac hypertrophy is a phenotypic alteration of the heart to compensate for loss of function after myocardial infarction or in association with chronic stress, as in hypertension[1,2,3]. In response to pro-hypertrophic stimuli, cardiomyocytes activate signaling pathways such as calcineurin/NFAT that favor their growth and increase their contractile function[4]. Activation of these pathways triggers reprogramming of gene expression in cardiomyocytes, including fetal genes such as the beta-myosin heavy chain (Myhβ)[5]. IP3R1 has been shown to be a Herpud[1] target[20] with the ability to regulate intracellular Ca2+ levels in neuron and HeLa cell lines[20,21] This ability suggests a potential role in cardiac IP3R degradation, which occurs via the proteasome pathway[22]. The goal of this study was to elucidate the role of Herpud[1] in cardiac pathophysiology and to assess whether Herpud[1] might serve as a novel therapeutic target in pathological cardiac hypertrophy
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