Activation of the bitter taste sensor TRPM5 prevents high salt-induced cardiovascular dysfunction

Abstract

High salt intake is a known risk factor of cardiovascular diseases. Our recent study demonstrated that long-term high salt intake impairs transient receptor potential channel M5 (TRPM5)-mediated aversion to high salt concentrations, consequently promoting high salt intake and hypertension; however, it remains unknown whether TRPM5 activation ameliorates cardiovascular dysfunction. Herein we found that bitter melon extract (BME) and cucurbitacin E (CuE), a major compound in BME, lowered high salt-induced hypertension. Long-term BME intake significantly enhanced the aversion to high salt concentrations by upregulating TRPM5 expression and function, eventually decreasing excessive salt consumption in mice. Moreover, dietary BME ameliorated high salt-induced cardiovascular dysfunction and angiotensin II-induced hypertension in vivo. The mechanistic evidence demonstrated that dietary BME inhibited high salt-induced RhoA/Rho kinase pathway overactivation, leading to reduced phosphorylation levels of myosin light chain kinase and myosin phosphatase targeting subunit 1. Furthermore, CuE inhibited vasoconstriction by attenuating L-type Ca2+ channel-induced Ca2+ influx in vascular smooth muscle cells. To summarize, our findings indicate that dietary BME has a beneficial role in antagonizing excessive salt consumption and thus appears promising for the prevention of high salt-induced cardiovascular dysfunction.

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Acknowledgements

We thank Lijuan Wang and Tingbing Cao for their technical assistance. This work was supported by grants from the National Natural Science Foundation of China (81721001, 81630015, 31701023) and National Key Research and Development Project (2018YFA0800601).

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Correspondence to Zhiming Zhu.

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Supporting Information

Figure S1 Water intake, urinary sodium excretion, and body weight of mice.

Figure S2 Effects of CuE on the prevention of apoptosis and fibrosis in H9C2 cardiomyocytes.

Figure S3 Effects of CuE on vasodilation of isolated mesenteric arteries or aortic rings.

Figure S4 Effects of CuE on vasoconstriction of isolated mesenteric arteries.

Table S1 EC50 and Emax values for phenylephrine (PE)- or U46619-induced contraction in mesenteric arteries from C57 mice treated with corresponding interventions

Table S2 EC50 and Emax values for acetylcholine (Ach) or nitroglycerin (NTG)-induced relaxations in mesenteric arteries from C57 mice treated with indicated interventions

Table S3 Characteristics of CuE-induced relaxation in different vasoconstrictors

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Wu, H., Cui, Y., He, C. et al. Activation of the bitter taste sensor TRPM5 prevents high salt-induced cardiovascular dysfunction. Sci. China Life Sci. 63, 1665–1677 (2020). https://doi.org/10.1007/s11427-019-1649-9

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  • transient receptor potential channel M5
  • bitter melon extract
  • cardiovascular dysfunction