A1964 TRPP3 knockout promotes cardiac hypertrophy through modulation of mitochondrial calcium homeostasis in mice

Abstract

Objectives: High intake of salt is an independent risk factor for cardiac hypertrophy. TRPP3 acts as a “sour” sensor in taste cells, and its potential role in the cardiovascular system is not known. We investigated the role of TRPP3 in high salt-induced cardiac hypertrophy. Methods: Two-month male TRPP3 knockout (TRPP3−/−) mice and their wild-type (WT) littermates were fed a normal diet (0.4% NaCl) or high-salt diet (HSD; 8% NaCl) diet for 24 weeks. Cardiac hypertrophy was examined and cardiomyocyte hypertrophy assayed by wheat germ agglutinin (WGA) staining and detection of protein levels of hypertrophic markers. H9c2 cardiomyocytes were stained with Fura-2AM or Rhod-2AM fluorescence indicators for detection of cytosolic and cardiac mitochondrial calcium ions (Ca2+), respectively. Expression of the mitochondrial Ca2+channelsNCX1, NHE1, MCU and LETM1wasdetected by western blotting. Results: High salt intake increased the HW/BW ratio and HW/TL ratio of WT mice significantly, and this was exacerbated by TRPP3 knockout. Consistently, WGA staining revealed that the cardiomyocyte hypertrophy induced by a HSD was exacerbated markedly in TRPP3−/− mice, and this was accompanied by higher expression of the hypertrophic markers β-MHC, ANP and BNP, compared with WT mice. Cytosolic and mitochondrial Ca2+uptake in H9c2 cardiomyocytes was reduced significantly by TRPP3 knockdown. TRPP3 deficiency resulted in increased expression of NCX1 and NHE1 without affecting expression of MCU and LETM1 in cardiomyocytes. Conclusion: We identified TRPP3 as a novel regulator of pathologic cardiac hypertrophy. The reduced Ca2+influx in cardiomyocytes and upregulation of expression of NCX1 and NHE1 contribute to the pro-hypertrophic effect of TRPP3 knockout.