Study on the mechanism of trimethylamine oxide damaging cardiac function in mice with hypertrophic cardiomyopathy

doi:10.3969/j.issn.1674-8115.2024.03.004

Abstract

Abstract:

Objective ·To investigate the effects of trimethylamine oxide (TMAO) on cardiac function in mice with hypertrophic cardiomyopathy (HCM) and its potential molecular mechanism. Methods ·Mice with myosin heavy chain 6 (Myh6) c.1211G>A (p.R404Q^+/-) point mutation were used as the animal model. According to dietary supplementation of TMAO and TMAO inhibitor iodomethylcholine (IMC), the wild type (WT) mice and HCM mice were divided into WT group, HCM group (HCM-1 group, HCM-2 group), WT+TMAO group, HCM+TMAO group and HCM+IMC group, respectively. Left ventricular fraction shortening (FS) and left ventricular posterior wall thickness (LVPW) were assessed by echocardiography in all mice. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum TMAO concentration of mice in the HCM-1 group and WT group. The regularity of myocardial cell arrangement of mice was evaluated by hematoxylin and eosin staining (HE staining). The proportion of myocardial fibrosis was evaluated by Masson staining. The activity of protein kinase A (PKA) in mouse myocardial tissue was detected by PKA kit. The expression of ryanodine receptor 2 (RyR2) and p-RyR2(S2808) in mouse myocardial tissue was detected by Western blotting. Results ·The results of echocardiography showed that at 12 months of age, the FS of mice in the WT+TMAO group and HCM+TMAO group were lower than those in the corresponding WT group and HCM-1 group, respectively (P<0.05). The LVPW of mice in the HCM+TMAO group was higher than that in the HCM-1 group, while the LVPW of mice in the HCM+IMC group was lower than that in the HCM-2 group (P<0.05). ELISA results showed that the serum TMAO concentration of mice in the HCM-1 group was higher than that in the WT mice (P<0.05). The results of HE staining and Masson staining showed that the HCM+TMAO group had a lower degree of regular arrangement of cardiomyocytes and a higher proportion of fibrosis than the HCM-1 group, while the HCM+IMC group had a higher degree of regular arrangement of cardiomyocytes and a lower proportion of fibrosis than the HCM-2 group (P<0.05). The results of PKA assay showed that the PKA activity in the myocardial tissue of mice in the WT+TMAO group and HCM+TMAO group increased after TMAO treatment, while the PKA activity in the myocardial tissue of mice in the HCM+IMC group decreased (P<0.05). Western blotting results showed that the expression of p-RyR2(S2808) in the myocardial tissue of the WT+TMAO group and HCM+TMAO group mice increased, while it was decreased in the HCM+IMC group mice (P<0.05); however, there was no difference in RyR2 expression among the groups. Conclusion ·TMAO can increase the activity of PKA and induce the phosphorylation of RyR2 at S2808, which can cause ventricular remodeling and impair cardiac function in HCM mice.

Key words: hypertrophic cardiomyopathy (HCM), trimethylamine oxide (TMAO), protein kinase A (PKA), ryanodine receptor 2 (RyR2)

CLC Number:

R542.2

JIN Bu, CHEN Hanzhang, XU Hudong, CHEN Wanyu, YUAN Ying, ZHAO Tingting, HUANG Xiaolei, HE Jialu, YU Hong. Study on the mechanism of trimethylamine oxide damaging cardiac function in mice with hypertrophic cardiomyopathy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(3): 325-333.

Figures/Tables 5

Fig 1 Effects of TMAO and IMC on cardiac function and LPVW in each group of mice

Fig 2 Detection of serum TMAO concentration of mice in the WT group and HCM-1 group

Fig 3 Effects of TMAO and IMC on the regularity of myocardial cell arrangement and the proportion of myocardial fibrosis in each group of mice

Fig 4 Differences of PKA activity in myocardium tissue of mice in each group

Fig 5 Detection of RyR2 and p-RyR2(S2808) expression in myocardium tissue of mice in each group

TrendMD

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