Taurine protects against cardiac dysfunction induced by pressure overload through SIRT1–p53 activation

doi:10.1016/j.cbi.2020.108972

Chemico-Biological Interactions

Volume 317, 1 February 2020, 108972

https://doi.org/10.1016/j.cbi.2020.108972 Get rights and content

Highlights

•
Taurine can improve cardiac function of HF mice.
•
Taurine concentration-dependently activated the SIRT1 expression in TAC mice.
•
Taurine inhibited pressure overload-induced p53 acetylation via a SIRT1 pathway.

Abstract

Background

Heart failure (HF) is an epidemic disease with increased incidence annually. It has been reported that taurine can improve cardiac function. This study investigated the cardioprotective effects of taurine in pressure-loaded HF mice and elucidated the possible mechanism.

Methods

HF models were established by transverse aortic constriction (TAC). Animals were treated with either taurine for 9 weeks and/or the SIRT1 inhibitor EX527 (5 mg/kg/day, every 2days) after TAC operation. Cardiac function and geometry were revealed by echocardiography. Myocardial hypertrophy and fibrosis were assessed using Fluorescent wheat germ agglutinin (WGA) staining and Masson's trichrome staining. Western blot and RT-PCR were performed to elucidate the expression of target proteins and genes respectively. Apoptosis in cardiomyocytes was detected by TUNEL staining. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD) and malonyldialdehyde (MDA) and reactive oxygen species (ROS). Taurine concentrations and NAD⁺/NADH ratio were determined by taurine and NAD⁺/NADH assay kit.

Results

Taurine notably relieved cardiac dysfunction after TAC. The mechanisms were attributed to reduced myocyte hypertrophy and fibrosis, and alleviated apoptosis and oxidative stress. Meanwhile, taurine increased NAD+/NADH ratio，promoted the expression of SIRT1 and suppressed p53 acetylation. However, EX-527(inhibitor of SIRT1) decreased NAD⁺/NADH ratio and increased acetyl-p53 levels, and abolished the cardioprotective effects of taurine on mice subjected to TAC and increased apoptosis and oxidative stress.

Conclusion

The mechanism responsible for cardiac-protective effects of taurine in HF induced by pressure overload is associated with the activation of the SIRT1–p53 pathway.

Introduction

Heart failure (HF) is one of the most common illnesses that severely harms the public health, the symptoms of which include impaired systolic and/or diastolic function and various clinical signs such as fatigue, limitations in exercise tolerance and fluid accumulation [1]. Nowadays, drug therapy for HF mainly contains diuretics, β-adrenoceptor antagonists, ACEI, ARB, ARNI and digitalis glycosides [2]. Despite the upward trend in the development of treatments for HF, morbidity and mortality continue to increase in Western countries [3]. Furthermore, HF patients with reduced ejection fraction had been reported to spend a large proportion of time and amount of money in hospitals and other medical facilities [4]. Consequently, it is imperative to develop better treatments for HF.

Taurine, one of the major free intracellular β-amino acids, is widely distributed in human and mammalian tissues, playing an essential role in maintaining cellular integrity in heart, muscles, retina, and central nervous system [5,6]. It is reported that taurine has beneficial actions in chronic HF of several animal models, such as iron overload-induced, cardiomyopathic model, and taurine depletion in some species can lead to dilated cardiomyopathy and HF [7,8]. Our preliminary experiment also suggested that taurine could improve cardiac function in mouse model of transverse aortic constriction (TAC) with HF but the result has not been proved and the mechanism remains unclear. Therefore, we designed this study to explore the cardioprotective effects of taurine in an established mouse model of TAC and to investigate the cardioprotective mechanism of taurine.

Section snippets

Experimental animals and reagents

Adult (8-week-old) male C57BL/6 mice weighing 18–21 g were obtained from the Air Force Military Medical University. Taurine and 40, 6-diamino-2-phenylindole (DAPI) were purchased from Sigma-Aldrich (St. Louis, MO, USA). The BCA protein assay kit (Shanghai Beyotime Biotechnology. Co. Ltd, Nanjing, China). SIRT1, acetylated p53 at Lys382 (Ac-p53(Lys382)), cleaved caspase-3, and cleaved caspase-9 antibodies were purchased from Cell Signaling Technology (Boston, MA, USA). cTnT, p53, p53 (phospho

Taurine prevented deterioration in cardiac function

Echocardiography was used for cardiac function evaluation in all groups and revealed increased LVEDD and LVESD in the TAC group compared with those in the SHAM group (P < 0.05; Fig. 1b c). LVEF and LVFS, which were markers of cardiac performance, were more significantly decreased in the TAC group than in the SHAM group (P < 0.05; Fig. 1d e). Taurine (0.5–1.5 g/kg/d) treatment increased LVEF and LVFS and decreased LVEDD and LVESD in mice subjected to TAC (P < 0.05; Fig. 1b–e). Secondly, the

Discussion

HF is one of the most common fatal syndromes. Despite the development of pharmacological agents and new nonpharmacological techniques to prevent and treat HF, the mortality rate in patients with symptomatic HF remains high [17]. It is widely considered that taurine can improve cardiac function [18,19]. Mechanisms underlying the cardioprotective effects of taurine include the regulation of antioxidation, energy metabolism, gene expression, endoplasmic reticulum stress, neuromodulation, and

Conclusions

In conclusion, our study provides strong evidence that taurine can relieve oxidative stress, reduced apoptosis, attenuate myocardial hypertrophy and fibrosis, and improve cardiac function in HF mice. These effects are related to the upregulation of SIRT1 levels and the inhibition of downstream p53 and oxidative stress. These data suggest the association between the SIRT1–p53 pathway and the myocardial protection provided by taurine.

CRediT authorship contribution statement

Jing Liu: Conceptualization, Methodology, Writing - original draft, Validation, Formal analysis, Data curation. Yongfei Ai: Writing - review & editing, Validation. Xiaolin Niu: Supervision, Investigation, Funding acquisition. Fujun Shang: Software, Methodology, Validation. Zhili Li: Validation, Formal analysis. Hui Liu: Validation, Formal analysis. Wei Li: Formal analysis, Data curation. Wenshuai Ma: Data curation. Ruirui Chen: Visualization. Ting Wei: Visualization. Xue Li: Funding

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (81570227), Young Science and Technology Star Foundation of Shaanxi Province (2015KTXX-52).

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Taurine protects against cardiac dysfunction induced by pressure overload through SIRT1–p53 activation

Highlights

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Experimental animals and reagents

Taurine prevented deterioration in cardiac function

Discussion

Conclusions

CRediT authorship contribution statement

Declaration of competing interest

Acknowledgments

Int. J. Cardiol.

JACC Heart Fail

J. Am. Coll. Cardiol.

Transl. Res.

Free Radic. Biol. Med.

Cell

Cell

Mol. Cell

Int. J. Cardiol.

Toxicol. Appl. Pharmacol.

Pharmacol. Ther.

Biochim. Biophys. Acta

Int. J. Biol. Macromol.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Heart failure with reduced ejection fraction

Nat Rev Dis Primers

How can we cure a heart "in flame"? A translational view on inflammation in heart failure

Basic Res. Cardiol.

Effect of taurine on ischemia-reperfusion injury

Amino Acids

Review: taurine: a "very essential" amino acid

Mol. Vis.

The effect of taurine on chronic heart failure: actions of taurine against catecholamine and angiotensin II

Amino Acids

Tissue taurine depletion induces profibrotic pattern of gene expression and causes aging-related cardiac fibrosis in heart in mice

Biol. Pharm. Bull.

Melatonin receptor-mediated protection against myocardial ischemia/reperfusion injury: role of SIRT1

J. Pineal Res.

The Sir2 family of protein deacetylases

Annu. Rev. Biochem.

Pathophysiology of cardiorenal syndrome in patients with heart failure: potential therapeutic targets

Am. J. Physiol. Heart Circ. Physiol.

Taurine supplementation improves functional capacity, myocardial oxygen consumption, and electrical activity in heart failure

J. Diet. Suppl.