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Herpud1 negatively regulates pathological cardiac hypertrophy by inducing IP3 receptor degradation
Natalia Torrealba1, Mario Navarro-Marquez1, Valeria Garrido1
1Advanced Center for Chronic Disease (ACCDiS) & Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Santiago, Chile.
Insights
Herpud1 negatively regulates cardiac hypertrophy by controlling inositol 1,4,5-trisphosphate receptor (IP3R) levels. Its absence causes cardiac hypertrophy and dysfunction, highlighting Herpud1
Area of Science:
- Cardiovascular Biology
- Molecular Cell Biology
- Endoplasmic Reticulum-Associated Degradation (ERAD)
Background:
- Cardiac hypertrophy is a pathological response to stress.
- Inositol 1,4,5-trisphosphate receptor (IP3R) synthesis and degradation impact cardiac hypertrophy.
- Herpud1, an ERAD component, is involved in IP3R1 degradation and calcium signaling, but its cardiac role is uncharacterized.
Purpose of the Study:
- To investigate the role of Herpud1 in cardiac hypertrophy.
- To test the hypothesis that Herpud1 negatively regulates cardiac hypertrophy by modulating IP3R protein levels.
Main Methods:
- Utilized Herpud1-knockout mouse models.
- Employed cultured rat cardiomyocytes treated with Herpud1 siRNA.
- Assessed cardiac hypertrophy, cardiac dysfunction, hypertrophic markers, IP3R levels, and intracellular calcium concentrations.
Main Results:
- Herpud1-knockout mice displayed cardiac hypertrophy and dysfunction.
- Reduced Herpud1 levels in cardiomyocytes elevated hypertrophic markers.
- IP3R levels increased in both Herpud1-knockout mice and siRNA-treated cardiomyocytes, alongside elevated cytosolic and nuclear calcium.
Conclusions:
- Herpud1 deficiency leads to a pathological hypertrophic phenotype.
- Herpud1 acts as a novel negative regulator of pathological cardiac hypertrophy.
- Regulation of IP3R protein levels by Herpud1 is a key mechanism in cardiac hypertrophy.
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.