Metformin attenuates angiotensin II‐induced TGFβ1 expression by targeting hepatocyte nuclear factor‐4‐α

Ruifei, Chen; Feng, Yenan; Wu, Jimin; Song, Yao; Li, Hao; Shen, Qiang; Li, Dan; Zhang, Jianshu; Lu, Zengjun; Xiao, Han; Zhang, Youyi

doi:10.1111/bph.13753

Cited by 31 publications

(22 citation statements)

References 35 publications

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“…Metformin is also an insulin sensitizer and may play a protective role in the intestinal lumen through a variety of mechanisms (Flory and Lipska, 2019;Horakova et al, 2019). Metformin can also reduce low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels (Xu et al, 2015;Weng et al, 2020); inhibit inflammatory responses (such as inhibiting the activation of nuclear factor kappa B [NF-kB] and interleukin-1b ) (Isoda et al, 2006;Deng et al, 2018); improve vascular endothelial function (activate 5'-adenosine monophosphateactivated protein kinase [AMPK], increase nitric oxide [NO] synthesis) (Nafisa et al, 2018;Sardu et al, 2019); inhibit cardiac remodeling (such as inhibiting cardiomyocytes apoptosis and cardiac fibrosis) (Sasaki et al, 2009;Chen R. et al, 2018). These suggest that metformin has a cardiovascular protective effect, but a comprehensive understanding of the mechanism of action of metformin is still lacking (Rena et al, 2017;Flory and Lipska, 2019).…”

Section: Introductionmentioning

confidence: 99%

Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function

Mingying

et al. 2020

Front. Pharmacol.

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Metformin has been used in diabetes for more than 60 years and has excellent safety in the therapy of human type 2 diabetes (T2D). There is growing evidence that the beneficial health effects of metformin are beyond its ability to improve glucose metabolism. Metformin not only reduces the incidence of cardiovascular diseases (CVD) in T2D patients, but also reduces the burden of atherosclerosis (AS) in pre-diabetes patients. Vascular smooth muscle cells (VSMCs) function is an important factor in determining the characteristics of the entire arterial vessel. Its excessive proliferation contributes to the etiology of several types of CVD, including AS, restenosis, and pulmonary hypertension. Current studies show that metformin has a beneficial effect on VSMCs function. Therefore, this review provides a timely overview of the role and molecular mechanisms by which metformin acts through VSMCs to protect CVD.

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Section: Introductionmentioning

confidence: 99%

Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function

Mingying

et al. 2020

Front. Pharmacol.

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“…The United Kingdom Prospective Diabetes Study (UKPDS) indicated that metformin had cardiovascular protective effects beyond reducing blood glucose levels (Ovalle, 2009;Rojas and Gomes, 2013;Natali et al, 2019). By further detecting AMPK activation, it was found that metformin could markedly decrease transforming growth factor-b1 production by inhibiting HNF4a, and ultimately suppressed cardiac fibrosis (Chen et al, 2018). Moreover, the positive effects of metformin have been indicated in the treatment of a prolonged QT interval in a diabetic state.…”

Section: Introductionmentioning

confidence: 99%

Metformin Shortens Prolonged QT Interval in Diabetic Mice by Inhibiting L-Type Calcium Current: A Possible Therapeutic Approach

Wang

Lü

et al. 2020

Front. Pharmacol.

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The incidence and mortality of cardiovascular disease in diabetic patients are 2-3 times higher than those in non-diabetic patients. Abnormal function of the L-type calcium channel in myocardial tissue might result in multiple cardiac disorders such as a prolonged QT interval. Therefore, QT prolongation is an independent risk factor of cardiovascular disease in patients with diabetes mellitus. Metformin, a hypoglycemic agent, is widely known to effectively reduce the occurrence of macrovascular diseases. The aim of the present study was to evaluate the effect of metformin on prolonged QT interval and to explore potential ionic mechanisms induced by diabetes. Diabetic mouse models were established with streptozotocin and an electrocardiogram was used to monitor the QT interval after 4 weeks of metformin treatment in each group. Action potential duration (APD) and L-type calcium current (I Ca-L) were detected by patch-clamp in isolated mice ventricular cardiomyocytes and neonatal cardiomyocytes of mice. The expression levels of CACNA1C mRNA and Cav1.2 were measured by real-time PCR, western blot and immunofluorescence. A shortened QT interval was observed after 4 weeks of metformin treatment in diabetic mice. Patch-clamp results revealed that both APD and I Ca-L were shortened in mouse cardiomyocytes. Furthermore, the expression levels of CACNA1C mRNA and Cav1.2 were decreased in the metformin group. The same results were also obtained in cultured neonatal mice cardiomyocytes. Overall, these results verify that metformin could shorten a prolonged QT interval by inhibiting the calcium current, suggesting that metformin may play a role in the electrophysiology underlying diabetic cardiopathy.

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“…These data mining findings suggest that APQ4 may not directly impact the transcription of TGFB1. On another hand, according still to the MEM database and webtool, AQP4 tightly co-expresses with angiotensinogen (AGT) (p-value: 2.95 −41 , Pearson correlation test), a gene upregulated in MS spinal cords [11] and extensively shown to promote the TGFB1 pathway [26][27][28][29]. Similarly in mice, Aqp4 tightly co-expresses with Agt (p-value: 5.85 −21 , Pearson correlation test).…”

mentioning

confidence: 99%

“…Similarly in mice, Aqp4 tightly co-expresses with Agt (p-value: 5.85 −21 , Pearson correlation test). Of note, Angiotensin II, the main active metabolite of angiotensinogen, not only stimulates the transcription of TGFB1 [26,29] but exerts short-term activating effects on SMADs [30][31][32], the transducing molecules of the TGF-beta pathway. Along this line, under conditions of acute neuronal insult, the engagement of the angiotensin II receptor type 1 on murine astrocytes is mandatory to contain the influx of blood leucocytes through the blood brain barrier [33].…”

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confidence: 99%

The Demonstration of an Aqp4/Tgf-Beta 1 Pathway in Murine Astrocytes Holds Implications for Both Neuromyelitis Optica and Progressive Multiple Sclerosis

Nataf

2020

IJMS

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The role exerted by Aquaporin 4 (AQP4) as a regulator of astrocyte immune functions has been poorly explored. A recent report demonstrates that under neuroinflammatory conditions, the expression of Aqp4 on murine astrocytes is mandatory for the effective control of acute inflammation in the central nervous system. Such an immunomodulatory function appears to be mediated by a promotion of the transforming growth factor beta 1 (Tgfb1) pathway. Here, these results are discussed in the context of neuromyelitis optica (NMO) and multiple sclerosis (MS) progressive forms. It is proposed that NMO and progressive MS might rely on opposite molecular mechanisms involving, in NMO, an acutely-defective AQP4/TGFB1 pathway and, in progressive MS, a chronically-stimulated AQP4/TGFB1 pathway. Data supporting the involvement of angiotensin II as a molecular link between AQP4 and TGFB1 are also reviewed.

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Metformin attenuates angiotensin II‐induced TGFβ1 expression by targeting hepatocyte nuclear factor‐4‐α

Abstract: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Cited by 31 publications

References 35 publications

Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function

Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function

Metformin Shortens Prolonged QT Interval in Diabetic Mice by Inhibiting L-Type Calcium Current: A Possible Therapeutic Approach

The Demonstration of an Aqp4/Tgf-Beta 1 Pathway in Murine Astrocytes Holds Implications for Both Neuromyelitis Optica and Progressive Multiple Sclerosis

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