Trimetazidine inhibits cardiac fibrosis by reducing reactive oxygen species and downregulating connective tissue growth factor in streptozotocin‑induced diabetic rats

Zhao, Yunyue; Li, Suhua; Quan, Enxi; Zhang, Hui; Wu, Yong-Xiang; Luo, Yun; Peng, Long; Wang, Jiarui; Zhu, Jun; Liu, Jinlai

doi:10.3892/etm.2019.7705

Cited by 18 publications

(17 citation statements)

References 37 publications

(44 reference statements)

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“…In addition, the effect of trimetazidine on heart failure is not limited to cardiomyocytes, and clinical studies have found that trimetazidine also improves EDR ( Belardinelli et al, 2007 ) and reduces inflammation ( Shao et al, 2016 ) in heart failure. Basic studies have also shown the protective effects of trimetazidine on non-cardiomyocytes, including antifibrotic effects ( Zhao et al, 2019 ). Therefore, exploring the effect of trimetazidine on non-cardiomyocytes will be important in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…In an animal model of heart failure produced by transverse aortic constriction surgery, the expression of CTGF in rats treated with trimetazidine decreased by 34% compared to that in the normal saline group. ROS, which are negatively regulated by trimetazidine, induce the synthesis of CTGF ( Zhao et al, 2019 ). Trimetazidine can improve the activity of NADPH oxidase and reduce the expression of ROS by regulating the translocation of the Rac1 subunit of NAPDH oxidase ( Liu et al, 2010 ).…”

Section: Basic Research Of Trimetazidine In Heart Failurementioning

confidence: 99%

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Trimetazidine in Heart Failure

et al. 2021

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Heart failure is a systemic syndrome caused by multiple pathological factors. Current treatments do not have satisfactory outcomes. Several basic studies have revealed the protective effect of trimetazidine on the heart, not only by metabolism modulation but also by relieving myocardial apoptosis, fibrosis, autophagy, and inflammation. Clinical studies have consistently indicated that trimetazidine acts as an adjunct to conventional treatments and improves the symptoms of heart failure. This review summarizes the basic pathological changes in the myocardium, with an emphasis on the alteration of cardiac metabolism in the development of heart failure. The clinical application of trimetazidine in heart failure and the mechanism of its protective effects on the myocardium are carefully discussed, as well as its main adverse effects. The intention of this review is to highlight this treatment as an effective alternative against heart failure and provide additional perspectives for future studies.

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Section: Discussionmentioning

confidence: 99%

Section: Basic Research Of Trimetazidine In Heart Failurementioning

confidence: 99%

Trimetazidine in Heart Failure

et al. 2021

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“…Trimetazidine is an anti-anginal agent that selectively inhibits the activity of mitochondrial long-chain 3-ketoacyl-CoA thiolase to cause inhibition of free-fatty-acid oxidation and promotion of glucose oxidation [80]. Trimetazidine was able to oppose increased collagen synthesis by isolated neonatal rat cardiac fibroblasts in response to HG, likely via downregulation of connective tissue growth factor and oxidative stress [81]. Importantly, trimetazidine reduced cardiac fibrosis in the STZ model of type 1 diabetes.…”

Section: Trimetazidinementioning

confidence: 99%

The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function

Levick

Widiapradja

2020

IJMS

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Diabetic cardiomyopathy involves remodeling of the heart in response to diabetes that includes microvascular damage, cardiomyocyte hypertrophy, and cardiac fibrosis. Cardiac fibrosis is a major contributor to diastolic dysfunction that can ultimately result in heart failure with preserved ejection fraction. Cardiac fibroblasts are the final effector cell in the process of cardiac fibrosis. This review article aims to describe the cardiac fibroblast phenotype in response to high-glucose conditions that mimic the diabetic state, as well as to explain the pathways underlying this phenotype. As such, this review focuses on studies conducted on isolated cardiac fibroblasts. We also describe molecules that appear to oppose the pro-fibrotic actions of high glucose on cardiac fibroblasts. This represents a major gap in knowledge in the field that needs to be addressed.

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“…In this study, diastolic dysfunction was evident in diabetic mice after 26 weeks of diabetes. This impairment developed in conjunction with myocardial fibrosis, a characteristic that has been reported in cardiac biopsies of patients with type 2 diabetes ( Shimizu et al, 1993 ), as well as in several experimental models of diabetes ( Wang et al, 2017 ; Tsai et al, 2018 ; Zhao et al, 2019 ).…”

Section: Discussionmentioning

confidence: 74%

Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy

et al. 2021

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People affected by diabetes are at an increased risk of developing heart failure than their non-diabetic counterparts, attributed in part to a distinct cardiac pathology termed diabetic cardiomyopathy. Mitochondrial dysfunction and excess reactive oxygen species (ROS) have been implicated in a range of diabetic complications and are a common feature of the diabetic heart. In this study, we sought to characterise impairments in mitochondrial structure and function in a recently described experimental mouse model of diabetic cardiomyopathy. Diabetes was induced in 6-week-old male FVB/N mice by the combination of three consecutive-daily injections of low-dose streptozotocin (STZ, each 55 mg/kg i.p.) and high-fat diet (42% fat from lipids) for 26 weeks. At study end, diabetic mice exhibited elevated blood glucose levels and impaired glucose tolerance, together with increases in both body weight gain and fat mass, replicating several aspects of human type 2 diabetes. The myocardial phenotype of diabetic mice included increased myocardial fibrosis and left ventricular (LV) diastolic dysfunction. Elevated LV superoxide levels were also evident. Diabetic mice exhibited a spectrum of LV mitochondrial changes, including decreased mitochondria area, increased levels of mitochondrial complex-III and complex-V protein abundance, and reduced complex-II oxygen consumption. In conclusion, these data suggest that the low-dose STZ-high fat experimental model replicates some of the mitochondrial changes seen in diabetes, and as such, this model may be useful to study treatments that target the mitochondria in diabetes.

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Trimetazidine inhibits cardiac fibrosis by reducing reactive oxygen species and downregulating connective tissue growth factor in streptozotocin‑induced diabetic rats

Cited by 18 publications

References 37 publications

Trimetazidine in Heart Failure

Trimetazidine in Heart Failure

The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function

Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy

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