Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results

Kang, Sang–Wook; Verma, Subodh; Hassanabad, Ali Fatehi; Teng, Guoqi; Belke, Darrell D.; Dundas, James; Guzzardi, David G.; Svystonyuk, Daniyil A.; Pattar, Simranjit S.; Park, Daniel S.J.; Turnbull, Jeffrey; Duff, Henry J.; Tibbles, Lee Anne; Cunnington, Ryan H.; Dyck, Jason R.B.; Fedak, Paul W.M.

doi:10.1016/j.cjca.2019.08.033

Cited by 93 publications

(52 citation statements)

References 45 publications

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“…FN1 encodes fibronectin, which plays essential roles in cell adhesion and migration, including the formation of the embryo, healing, blood clotting response, and host defense. The role of FN1 in DCM focuses on extracellular cellular matrix (ECM) remodeling [ 41 ]. As the target gene of miR-144 and miR-9, it can be concluded that the miR-144/FN1 and miR-9-3p/FN1 might be necessary in the progresses of myocardial fibrosis in DCM.…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Hub Genes and miRNAs in Dilated Cardiomyopathy

Huang

Wen

Wang

et al. 2020

BioMed Research International

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Purpose. The aim of this study is to identify hub genes and miRNAs by the miRNA-mRNA interaction network in dilated cardiomyopathy (DCM) disease. Methods. The differentially expressed miRNAs (DEMis) and mRNAs (DEMs) were selected using data of DCM patients downloaded from the GEO database (GSE112556 and GSE3585). Gene Ontology (GO) pathway analysis and transcription factor enrichment analysis were used for selecting DEMis, and the target mRNAs of DEMis were filtered by using miRDB, miRTarBase, and TargetScan. Cytoscape software was used to visualize the network between miRNAs and mRNAs and calculate the hub genes. GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to analyze the mRNAs in the regulatory network. Results. A total of 9 DEMis and 281 DEMs were selected, from which we reconstructed the miRNA-mRNA network consisting of 7 miRNAs and 51 mRNAs. The top 10 nodes, miR-144-3p, miR-363-3p, miR-9-3p, miR-21-3p, miR-144-5p, miR-338-3p, ID4 (inhibitor of DNA binding/differentiation 4), miR-770-5p, PIK3R1 (p85α regulatory subunit of phosphoinositide 3-kinase (PI3K)), and FN1 (fibronectin 1), were identified as important regulators. Conclusions. The study uncovered several important hub genes and miRNAs involved in the pathogenesis of DCM, among which, the miR-144-3p/FN1 and miR-9-3p/FN1 pathways may play an important role in myocardial fibrosis, which can help identify the etiology of DCM, and provide potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Hub Genes and miRNAs in Dilated Cardiomyopathy

Huang

Wen

Wang

et al. 2020

BioMed Research International

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“…101 Empagliflozin significantly attenuates TGFβ 1induced fibroblast activation and cell-mediated ECM remodeling, together with suppression of critical profibrotic markers, including COL1A1, ACTA2 (αSMA), CTGF, FN1, and MMP2 in vitro, which suggests antifibrotic effects with empagliflozin. 113 For personal use only.…”

Section: Sglt2 Inhibitors and Inflammation Factors And Cardiac Fibrosmentioning

confidence: 99%

<p>SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy</p>

Li¹,

Zhou²

2020

DDDT

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Diabetic cardiomyopathy (DCM) characterized by diastolic and systolic dysfunction independently of hypertension and coronary heart disease, eventually develops into heart failure, which is strongly linked to a high prevalence of mortality in people with diabetes mellitus (DM). Sodium-glucose cotransporter type2 inhibitors (SGLT2Is) are a novel type of hypoglycemic agent in increasing urinary glucose and sodium excretion. Excitingly, the EMPA-REG clinical trial proved that empagliflozin significantly reduced the relative risk of cardiovascular (CV) death and hospitalization for heart failure (HHF) in patients with type 2 DM (T2DM) plus CV disease (CVD). The EMPRISE trial showed that empagliflozin decreased the risk of HHF in T2DM patients with and without a CVD history in routine care. These beneficial effects of SGLT2Is could not be entirely attributed to glucose-lowering or natriuretic action. There could be potential direct mechanisms of SGLT2Is in cardioprotection. Recent studies have shown the effects of SGLT2Is on cardiac iron homeostasis, mitochondrial function, anti-inflammation, anti-fibrosis, antioxidative stress, and reninangiotensin-aldosterone system activity, as well as GlcNAcylation in the heart. This article reviews the current literature on the effects of SGLT2Is on DCM in preclinical studies. Possible molecular mechanisms regarding potential benefits of SGLT2Is for DCM are highlighted, with the purpose of providing a novel strategy for preventing DCM.

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“…Moreover, SGLT-2is or SGLT-2/1is can alleviate heart failure by reducing cytoplasmic sodium and calcium levels through inhibition of Na + /H + exchanger (NHE) 1 in the myocardium and/or NHE3 in proximal tubule (72,73). As for the cardiac structure remodeling during heart failure, SGLT-2is or SGLT-2/ 1is suppress collagen synthesis via increasing the activation of M2 macrophages and inhibiting myofibroblast differentiation, attenuates TGF-b1-induced fibroblast activation and suppress expression of key pro-fibrotic markers, including type I collagen, a-smooth muscle actin, connective tissue growth factor and matrix metalloproteinase 2, thus prevents or alleviate myocardial fibrosis (74,75), inhibit histone deacetylase and prevent pro-hypertrophic transcription pathways (76).…”

Section: Sglt-2is or Sglt-2/1ismentioning

confidence: 99%

The Effects of DPP-4 Inhibitors, GLP-1RAs, and SGLT-2/1 Inhibitors on Heart Failure Outcomes in Diabetic Patients With and Without Heart Failure History: Insights From CVOTs and Drug Mechanism

Pan

et al. 2020

Front. Endocrinol.

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Patients with type 2 diabetes (T2D) have a higher risk of heart failure (HF) than healthy people, and the prognosis of patients with diabetes and current or previous HF is worse than that of patients with only diabetes. We reviewed the HF outcomes in recently published cardiovascular outcome trials (CVOTs) of three new classes of anti-diabetic agents, namely, dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like-peptide 1 receptor agonists (GLP-1RAs), and sodium glucose cotransporter-2 inhibitors (SGLT-2is) or SGLT-2 and SGLT-1 dual inhibitors and divided the patients into two groups based on the history of HF (with or without) and analyzed their risks of HHF based on the receipt of the aforementioned anti-diabetes drug types. Since the follow-up period differed among the trials, we expressed the rate of HHF as events/1,000 person-years to describe the HF outcome. At last we pooled the data and analyzed their different effects and mechanisms on heart failure outcomes. Although DPP-4is did not increase the risk of HHF in T2D patients with a history of HF, they were associated with a significantly higher risk of HHF among patients without history of HF. Some GLP-1RAs reduced the risk of macrovascular events, but none of these drugs reduced the risk of HHF in patients with T2D irrespective of their HF history. It was not clarified whether SGLT-1/2is can improve the prognosis of macrovascular events in patients with T2D, but these drugs reduced the risk of HHF regardless of patients’ histories of HF. This information may be useful or referential for the “precise” selection of hyperglycemic medications. Further researches still needed to clarify the mechanisms of these anti-diabetic medications.

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Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results

Abstract: See editorial by Meagher et al., pages 464e466 of this issue.

Cited by 93 publications

References 45 publications

Integrated Analysis of Hub Genes and miRNAs in Dilated Cardiomyopathy

Integrated Analysis of Hub Genes and miRNAs in Dilated Cardiomyopathy

<p>SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy</p>

The Effects of DPP-4 Inhibitors, GLP-1RAs, and SGLT-2/1 Inhibitors on Heart Failure Outcomes in Diabetic Patients With and Without Heart Failure History: Insights From CVOTs and Drug Mechanism

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