Pharmacological and genetic inhibition of transient receptor potential melastatin-subfamily member 7 (Trpm7) channel in the carotid body attenuated intermittent hypoxia-induced hypertension

Abstract

RATIONALE: Obesity causes hypertension and sleep disordered breathing (SDB). Intermittent hypoxia (IH), a cardinal feature of SDB, also causes hypertension contributing to cardiovascular sequelae of obesity. The carotid body plays a role in the IH-induced hypertension. We have previously shown that obesity increases expression of the transient receptor potential melastatin-subfamily member 7 (TRPM7) channel in CB glomus cells and that knockdown of TRPM7 in CB treats hypertension in diet-induced obese mice. Our data in cell culture indicate that hypoxia increases TRPM7 expression. Therefore, we hypothesized that IH increases TRPM7 expression in CB and that pharmacological and genetic inhibition of Trpm7 in CB will treat IH-induced hypertension. Methods: 1) Pharmacological inhibition: We exposed male C57BL/6J mice to IH (n = 9) or air (n = 9) for 5 days and obtained continuous BP telemetry recording prior and after the exposure. Then we applied a long-acting TRPM7 inhibitor FTY720 or placebo to the CB area and repeated BP measurements before and after the 5-day IH or air exposure.2) Genetic inhibition: In another experiment, we knocked out Trpm7 gene expression in CB of male Trpm7 flox/flox mice by administering adenovirus carrying Cre-recombinase to the CB followed by BP recording during the 5-day IH or air exposure. RESULTS: We found that IH induced > 20-fold increase in Trpm7 mRNA expression in CB. IH increased BP from 102.9 ± 1.0 mmHg to 111.7 ± 1.1 mmHg. FTY720 hydrogel abolished the BP increase induced by IH. In Trpm7 flox/flox mice, IH also markedly increased BP prior to the adenoviral treatment from 101.9 ± 1.6 mmHg to 110.2 ± 4.0 mmHg. CB-specific Trpm7 knockout abolished IH-induced hypertension. CONCLUSION: We conclude that IH-induced upregulation of Trpm7 in CB contributes to the development of hypertension in IH and that IH-induced hypertension can be treated by pharmacological and genetic inhibition of Trpm7. 19CDA34700025, R01HL133100, R01HL128970. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.