Journal of Shanghai Jiao Tong University (Medical Science) >

2024 , Vol. 44 >Issue 3: 325 - 333

DOI: https://doi.org/10.3969/j.issn.1674-8115.2024.03.004

Basic research

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

  • Bu JIN ,
  • Hanzhang CHEN ,
  • Hudong XU ,
  • Wanyu CHEN ,
  • Ying YUAN ,
  • Tingting ZHAO ,
  • Xiaolei HUANG ,
  • Jialu HE ,
  • Hong YU
Expand
  • 1.Department of Pathology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201803, China
    2.Department of Pathology, Zhabei Central Hospital of Shanghai Jingan District, Shanghai 200070, China
    3.Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
YU Hong, E-mail: 1154879190@qq.com.

Received date: 2023-10-18

  Accepted date: 2024-01-31

  Online published: 2024-03-28

Supported by

Health Industry Clinical Research Project of Shanghai Municipal Health Commission(20224Y0234);Science and Technology Innovation Project of Shanghai Jiading District Jiangqiao Hospital(202228B)

Fold

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)

Cite this article

Bu JIN , Hanzhang CHEN , Hudong XU , Wanyu CHEN , Ying YUAN , Tingting ZHAO , Xiaolei HUANG , Jialu HE , Hong YU . 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 . DOI: 10.3969/j.issn.1674-8115.2024.03.004

References

1 MARON B J, DESAI M Y, NISHIMURA R A, et al. Diagnosis and evaluation of hypertrophic cardiomyopathy: JACC state-of-the-art review[J]. J Am Coll Cardiol, 2022, 79(4): 372-389.
2 OMMEN S R, MITAL S, BURKE M A, et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: executive summary: a report of the American college of cardiology/American heart association joint committee on clinical practice guidelines[J]. J Am Coll Cardiol, 2020, 76(25): 3022-3055.
3 MARON B J, GARDIN J M, FLACK J M, et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study[J]. Circulation, 1995, 92(4): 785-789.
4 HO C Y, CHARRON P, RICHARD P, et al. Genetic advances in sarcomeric cardiomyopathies: state of the art[J]. Cardiovasc Res, 2015, 105(4): 397-408.
5 TEEKAKIRIKUL P, ZHU W J, HUANG H C, et al. Hypertrophic cardiomyopathy: an overview of genetics and management[J]. Biomolecules, 2019, 9(12): 878.
6 RICHARDS E M, LI J, STEVENS B R, et al. Gut microbiome and neuroinflammation in hypertension[J]. Circ Res, 2022, 130(3): 401-417.
7 CANDELLI M, FRANZA L, CIANCI R, et al. The interplay between Helicobacter pylori and gut microbiota in non-gastrointestinal disorders: a special focus on atherosclerosis[J]. Int J Mol Sci, 2023, 24(24): 17520.
8 TANG W H W, NEMET I, LI X S, et al. Prognostic value of gut microbe-generated metabolite phenylacetylglutamine in patients with heart failure[J]. Eur J Heart Fail. 2023. doi: 10.1002/ejhf.3111.
9 ORGAN C L, OTSUKA H, BHUSHAN S, et al. Choline diet and its gut microbe-derived metabolite, trimethylamine N-oxide, exacerbate pressure overload-induced heart failure[J]. Circ Heart Fail, 2016, 9(1): e002314.
10 SHIH D M, WANG Z N, LEE R, et al. Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis[J]. J Lipid Res, 2015, 56(1): 22-37.
11 LI Z H, WU Z Y, YAN J Y, et al. Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis[J]. Lab Invest, 2019, 99(3): 346-357.
12 GREEN E M, WAKIMOTO H, ANDERSON R L, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice[J]. Science, 2016, 351(6273): 617-621.
13 RYU Y, JIN L, KEE H J, et al. Gallic acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through regulation of JNK2 signaling and Smad3 binding activity[J]. Sci Rep, 2016, 6: 34790.
14 TANG W H, WANG Z N, FAN Y Y, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis[J]. J Am Coll Cardiol, 2014, 64(18): 1908-1914.
15 DOBREV D, WEHRENS X H T. Role of RyR2 phosphorylation in heart failure and arrhythmias: controversies around ryanodine receptor phosphorylation in cardiac disease[J]. Circ Res, 2014, 114(8): 1311-1319; discussion1319.
16 CHANDRA M, RUNDELL V L, TARDIFF J C, et al. Ca(2+) activation of myofilaments from transgenic mouse hearts expressing R92Q mutant cardiac troponin T[J]. Am J Physiol Heart Circ Physiol, 2001, 280(2): H705-H713.
17 NAJAFI A, SCHLOSSAREK S, VAN DEEL E D, et al. Sexual dimorphic response to exercise in hypertrophic cardiomyopathy-associated MYBPC3-targeted knock-in mice[J]. Pflugers Arch, 2015, 467(6): 1303-1317.
18 HOUSER S R. Role of RyR2 phosphorylation in heart failure and arrhythmias: protein kinase A-mediated hyperphosphorylation of the ryanodine receptor at serine 2808 does not alter cardiac contractility or cause heart failure and arrhythmias[J]. Circ Res, 2014, 114(8): 1320-1327; discussion1327.
19 LEHNART S E, WEHRENS X H T, REIKEN S, et al. Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias[J]. Cell, 2005, 123(1): 25-35.
20 BETOCCHI S, HESS O M, LOSI M A, et al. Regional left ventricular mechanics in hypertrophic cardiomyopathy[J]. Circulation, 1993, 88(5 Pt 1): 2206-2214.
21 MARAS D, CHUNG R, DUNCAN A, et al. Patterns of cardiac dysfunction coinciding with exertional breathlessness in hypertrophic cardiomyopathy[J]. Int J Cardiol, 2013, 170(2): 233-238.
Options
Outlines

/

〈 〉