Destructive Role of TMAO in T-Tubule and Excitation-Contraction Coupling in the Adult Cardiomyocytes

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Heart failure (HF) is a disease with high morbidity and mortality. In patients with HF, decreased cardiac output and blood redistribution results in decreased intestinal perfusion and destruction of intestinal barrier. Microorganisms and endotoxins can migrate into the blood circulation, aggravating systemic inflammation and HF. Trimethylamine N-oxide (TMAO) is highly closed to the occurrence of HF. However, the exact mechanism between TMAO and HF remains unclear.

To investigate the role of TMAO in transverse-tubule (T-tubule) in the cultured cardiomyocytes.

T-tubule imaging and analysis detected T-tubule network in cardiomyocytes. Ca²⁺ handling dysfunction was identified by confocal Ca²⁺ imaging. Tubulin densification and polymerization were assessed by western blot and immunofluorescent staining of cardiomyocytes.

TMAO induced T-tubule network damage in cardiomyocytes and Ca²⁺ handling dysfunction in cardiomyocytes under the TMAO stress via promoting tubulin densification and polymerization and therefore Junctophilin-2 (JPH2) redistribution. Mice treated with TMAO represented cardiac dysfunction and T-tubule network disorganization.

TMAO impairs cardiac function via the promotion of tubulin polymerization, subsequent translocation of JPH2, and T-tubule remodeling, which provides a novel mechanism for the relationship between HF and elevated TMAO.