Metformin decreased myocardial fibrosis and apoptosis in hyperhomocysteinemia -induced cardiac hypertrophy

Zhao, Qinshuo; Song, Wei; Huang, Jingqiu; Wang, Dong; Xu, Changwu

doi:10.1016/j.retram.2020.103270

Cited by 19 publications

(20 citation statements)

References 29 publications

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“…Our findings are completely opposite from results in H9c2 cardiomyocytes (40). Others have demonstrated that HHcy could induce hypertrophy and apoptosis of cardiomyocytes, leading to cardiac fibrosis in mice fed with HMD for 12 weeks (41). In our study, however, the roles of Hcyinhibition of autophagy and apoptosis were observed in mice fed with HMD.…”

Section: Discussioncontrasting

confidence: 99%

Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway

Shi¹,

Zhao²,

Zhang³

et al. 2021

Ann Transl Med

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Section: Discussioncontrasting

confidence: 99%

Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway

Shi¹,

Zhao²,

Zhang³

et al. 2021

Ann Transl Med

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“…Although the possibility of improving the HF standard of care with epidrugs is still in its infancy, the BETonMACE study has provided promising results about the use of apabetalone in reducing hospitalization and cardiovascular death. Preclinical models of cardiac remodeling demonstrated that metformin, statins, SGLT2i, and PUFAs [41][42][43][44][45][46][47][48] can improve vascular health and cardiac fibrosis by modulating specific molecular pathways, and, in part, through downstream epigenetic interference, especially for hydralazine 39 and empagliflozin (Figure 2). 49 Of note, metformin and SGLT2i can impact on the "epigenetic memory" phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“… 10 Mechanistically, metformin may also have epigenetic-oriented effects through activating the AMP-activated protein kinase (AMPK) which, in turn, can phosphorylate and inhibit epigenetic enzymes such as histone acetyltransferases (HATs), class II HDAC, and DNA methyltransferases (DNMTs). 40 Both metformin 41 , 42 and statins 43 , 44 may reduce cardiac fibrosis; however, whether their beneficial effects are mediated by epigenetic-oriented responses has yet to be demonstrated. Furthermore, SGLT2i are a new group of oral drugs used for treating type 2 diabetes and its cardiovascular/renal complications.…”

Section: Repurposed Drugs With a Potential “Indirect” Epigenetic-oriented Interference For Management Of Hfmentioning

confidence: 99%

Epigenetic Therapies for Heart Failure: Current Insights and Future Potential

Napoli

Bontempo

Palmieri

et al. 2021

VHRM

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Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy ("epidrugs") is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.

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“…HHCY is characterized by an abnormally high level of homocysteine in the blood, which has been reported as an independent risk factor for several cardiovascular diseases ( 31 , 32 ). Previous studies have reported that HHCY accelerates the pathological cardiac remodeling by promoting myocardial interstitial and perivascular fibrosis ( 2 , 33 ). During pathological cardiac remodeling and cardiac fibrosis, CFs activate and secrete various matrix protein and proinflammatory cytokines including α-SMA, collagen I and Ⅲ, which can promote CF migration and proliferation ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…As closely associated to cardiac fibrosis and heart remodeling, hyperhomocysteinemia (HHCY) is generally known as a risk factor of cardiovascular diseases ( 2 ). Previous tudies have shown that HHCY can lead to myocardial interstitial and perivascular fibrosis and accelerate the progress of cardiac remodeling ( 2 , 3 ). However, although the unfavorable effects of HHCY on cardiovascular disease are well documented, the underlying mechanism of HHCY leading to cardiac fibrosis remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Se alleviates homocysteine‑induced fibrosis in cardiac fibroblasts via downregulation of lncRNA MEG3

Cui

et al. 2021

Exp Ther Med

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Selenium (Se) is considered to have antioxidant properties, which are beneficial for heart condition. Hyperhomocysteinemia (HHCY) has been suggested to potentially lead to heart failure and is characterized by cardiac fibrosis; however, investigation on the role of Se and HHCY in cardiac fibrosis is rare. Since previous studies demonstrated the important role of the long non-coding RNA maternally expressed 3 (MEG3) in some heart diseases, the present study aimed to determine how Se and MEG3 might exert regulatory effects on HCY-induced fibrosis in cardiac fibroblasts (CFs). Mouse CFs were isolated and treated with HCY and Se. The expression of α-smooth muscle actin (α-SMA), collagen I and III was detected by western blotting to reflect CF fibrosis. Reverse transcription-quantitative PCR was performed to determine the expression levels of MEG3. Inflammation and oxidative stress responses were analyzed by measuring TNF-α, IL-1β (ELISA) and reactive oxygen species levels (using a commercial kit), respectively. Cell Counting Kit-8 was used to evaluate CF proliferation. Total and phosphorylated (p) expression of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) was evaluated by western blotting. CFs were transfected with adenovirus expressing MEG3 short-hairpin RNA to knock down MEG3 expression. Se treatment downregulated the expression level of MEG3 in HCY-stimulated CFs, whilst inhibiting the inflammatory and oxidative stress response. Furthermore, Se inhibited the increased proliferation of CFs following HCY treatment. In addition, MEG3-knockdown in CFs could improve fibrosis caused by HCY. Furthermore, the ratios of p-JAK2/JAK2 and p-STAT3/STAT3 were decreased following treatment with Se or MEG3 silencing. Taken together, the findings from the present study suggested that Se may alleviate cardiac fibrosis by downregulating the expression of MEG3 and reducing the inflammatory and oxidative stress response in CFs. This suggests that Se may be a potential therapeutic option for treating cardiac fibrosis in the future.

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Metformin decreased myocardial fibrosis and apoptosis in hyperhomocysteinemia -induced cardiac hypertrophy

Cited by 19 publications

References 29 publications

Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway

Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway

Epigenetic Therapies for Heart Failure: Current Insights and Future Potential

Se alleviates homocysteine‑induced fibrosis in cardiac fibroblasts via downregulation of lncRNA MEG3

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