Author Correction: In vivo transduction of ETV2 improves cardiac function and induces vascular regeneration following myocardial infarction

Abstract Cardiac ischemia impairs angiogenesis in response to hypoxia, resulting in ventricular remodeling. Garcinoic acid (GA), the extraction from the plant garcinia kola, is validated to attenuate inflammatory response. However, the role of GA in heart failure (HF) and neovascularization after myocardial infarction (MI) is incompletely understood. The present study is striving to explore the role of GA and the potential mechanism of which in cardiac function after MI. SD rats were randomized into sham group, MI+vehicle group, and MI+GA group in vivo. Human umbilical endothelial cells (HUVECs) were cultured in vehicle or GA, and then additionally exposed to 2% hypoxia environment in vitro. MI rats displayed a dramatically reduced myocardial injury, cardiac function and vessel density in the peri-infarcted areas. GA delivery markedly improved cardiac performance and promoted angiogenesis. In addition, GA significantly enhanced tube formation in HUVECs under hypoxia condition. Furthermore, the expressions of pro-angiogenic factors HIF-1α, VEGF-A and bFGF, and pro-angiogenic proteins phospho-VEGFR2Tyr1175 and VEGFR2, as well as phosphorylation levels of Akt and eNOS were increased by GA treatment. In conclusion, GA preserved cardiac function after MI probably via promoting neovascularization. And the potential mechanism may be partially through upregulating the expressions of HIF-1α, VEGF-A, bFGF, phospho-VEGFR2Tyr1175 and VEGFR2 and activating the phosphorylations of Akt and eNOS.

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Abstract 56: Candesartan And Valsartan, Contrary To Irbesartan, Are Potent Biased Antagonists Of Adrenal (beta)arrestin-dependent, Angiotensin II Type 1 Receptor-induced Aldosterone Production And Improve Cardiac Function Post-myocardial Infarction

Circulation Research ◽

10.1161/res.115.suppl_1.56 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Anastasios Lymperopoulos ◽

Karlee Walklett ◽

Samalia Dabul ◽

Ashley Siryk ◽

Emmanuel Sturchler ◽

...

Keyword(s):

Myocardial Infarction ◽

Angiotensin Ii ◽

Cardiac Function ◽

G Protein ◽

Plasma Aldosterone ◽

Post Myocardial Infarction ◽

Aldosterone Production

Introduction: The scaffolding protein βarrestin1 (βarr1) by the angiotensin II (AngII) type 1 receptor (AT 1 R) mediates AngII-induced aldosterone production in vitro and physiologically in vivo, thereby exacerbating heart failure (HF) progression post-myocardial infarction (MI). Herein, we sought to investigate the relative potency of various AT 1 R antagonist drugs (sartans) at inhibiting βarr vs. G protein activation and hence aldosterone production in vitro and in vivo. We also investigated the alterations in plasma aldosterone levels conferred by these agents and their impact on cardiac function of post-MI rats. Methods: For the in vitro tests, transfected CHO and adrenocortical H295R cells were used. For in vivo studies, post-MI rats overexpressing βarr1 in their adrenals received 7-day-long treatments with the drugs of interest. Results: Among the sartans tested, candesartan and valsartan were the most potent βarr activation and βarr-mediated aldosterone production inhibitors in vitro, as well as the most “biased” antagonists towards βarr vs. G-protein inhibition. Conversely, losartan and irbesartan were the least potent βarr inhibitors and the least “biased” antagonists towards βarr inhibition. These in vitro findings were corroborated in vivo, since candesartan and valsartan, contrary to irbesartan, caused significant plasma aldosterone reductions in post-MI rats. Accordingly, cardiac ejection fraction (EF) and contractility were significantly augmented in candesartan- and valsartan-treated rats (EF: 41.1±1% and 40±1% respectively, vs. 35±0.3% for saline-treated), but further deteriorated in irbesartan-treated post-MI rats (EF: 32±1%, n=7 rats/group). Conclusions: These findings provide important insights that might aid pharmacotherapeutic decisions (i.e. individual agent selections) involving this commonly prescribed cardiovascular drug class (sartans).

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MicroRNA-326-5p enhances therapeutic potential of endothelial progenitor cells for myocardial infarction

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1413-8 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Xiaoting Li ◽

Xiang Xue ◽

Yuejun Sun ◽

Lei Chen ◽

Ting Zhao ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Western Blot ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Tube Formation ◽

Luciferase Reporter Assay ◽

Luciferase Reporter ◽

Reporter Assay

Abstract Background Our study sought to investigate the therapeutic effects and mechanisms of miR-326-5p-overexpressing endothelial progenitor cells (EPCs) on acute myocardial infarction (AMI). Methods Mouse EPCs were isolated, purified, and identified by flow cytometry and uptake of DiI-ac-LDL. The target gene of miR-326-5p was predicted using target prediction algorithms and verified by dual-luciferase reporter assay, RT-qPCR, and Western blot. After EPCs were transfected with the agomir or antagomir of miR-326-5p, tube formation assay and Matrigel plug angiogenesis assay were conducted in four groups (NC, miR-326-5p agomir, miR-326-5p antagomir, and miR-326-5p agomir+Wnt1 agonist). In addition, a mouse model of MI was established and treated with the injection of miR-326-5p-EPCs, miR-326-5p-EPCs+ Wnt1 agonist, EPCs-NC, or PBS/control into the peri-infarcted myocardium. Subsequently, cardiac function was monitored by echocardiography at 7 and 28 days postoperatively. Finally, the infarcted hearts were collected at 28 days, and the size of myocardial infarction was measured by Masson’s trichrome staining and the neovascularization in the peri-infarcted area was examined through immunofluorescence staining. Results Luciferase reporter assay indicated that Wnt1 was a direct target of miR-326-5p. Using RT-qPCR and Western blot analysis, we further demonstrated that the expression level of Wnt1 was negatively correlated with miR-326-5p expression in EPCs. Both in vitro study of tube formation assay and in vivo investigation of subcutaneous Matrigel plug assay revealed that the miR-326-5p agomir could significantly enhance the angiogenic capacity of EPCs, and this effect was partially inhibited by Wnt1 agonist. Meanwhile, miR-326-5p antagomir could obviously reduce the the angiogenic capacity of EPCs in vivo compared with that in the NC group. Moreover, the transplantation of miR-326-5p-overexpressing EPCs in the ischemic hearts of mice significantly enhanced the angiogenesis in the peri-infarcted zone and improved the cardiac function. However, the enhanced capacity of angiogenesis of miR-326-5p-overexpressing EPCs was remarkably neutralized by Wnt1 agonist, accompanied by the decreased improvement in cardiac function. Conclusion miR-326-5p significantly enhanced the angiogenic capacity of EPCs. Transplantation of miR-326-5p-overexpressing EPCs improved cardiac function for AMI therapy, which can be a novel strategy for enhancing therapeutic angiogenesis in ischemic heart diseases.

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Effects of In Vivo Administration of an Endothelial KCa Channel Activator on Recovery of Cardiac Function Following Acute Myocardial Infarction in Mice

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.04575 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Tae yeob Kim ◽

Darrell D. Belke ◽

Ramesh C. Mishra ◽

Andrew P. Braun

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Cardiac Function ◽

In Vivo Administration ◽

Channel Activator

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Lentiviral vector-mediated in vivo SERCA2a gene transfer improved cardiac function and remodeling of failing heart induced by myocardial infarction in the rat

Folia Pharmacologica Japonica ◽

10.1254/fpj.129.238 ◽

2007 ◽

Vol 129 (4) ◽

pp. 238-243

Author(s):

Masashi Arai ◽

Kazuo Niwano

Keyword(s):

Myocardial Infarction ◽

Gene Transfer ◽

Cardiac Function ◽

Lentiviral Vector ◽

Failing Heart

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Sacubitril/Valsartan Improves Cardiac Function and Decreases Myocardial Fibrosis Via Downregulation of Exosomal miR‐181a in a Rodent Chronic Myocardial Infarction Model

Journal of the American Heart Association ◽

10.1161/jaha.119.015640 ◽

2020 ◽

Vol 9 (13) ◽

Author(s):

Evgeniya Vaskova ◽

Gentaro Ikeda ◽

Yuko Tada ◽

Christine Wahlquist ◽

Marc Mercola ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cell ◽

Cardiac Function ◽

Pluripotent Stem Cell ◽

Myocardial Injury ◽

Induced Pluripotent Stem Cell ◽

Injury Model ◽

Induced Pluripotent

Background Exosomes are small extracellular vesicles that function as intercellular messengers and effectors. Exosomal cargo contains regulatory small molecules, including mi RNA s, mRNA s, lnc RNA s, and small peptides that can be modulated by different pathological stimuli to the cells. One of the main mechanisms of action of drug therapy may be the altered production and/or content of the exosomes. Methods and Results We studied the effects on exosome production and content by neprilysin inhibitor/angiotensin receptor blockers, sacubitril/valsartan and valsartan alone, using human‐induced pluripotent stem cell‐derived cardiomyocytes under normoxic and hypoxic injury model in vitro , and assessed for physiologic correlation using an ischemic myocardial injury rodent model in vivo. We demonstrated that the treatment with sacubitril/valsartan and valsartan alone resulted in the increased production of exosomes by induced pluripotent stem cell‐derived cardiomyocytes in vitro in both conditions as well as in the rat plasma in vivo. Next‐generation sequencing of these exosomes exhibited downregulation of the expression of rno‐miR‐181a in the sacubitril/valsartan treatment group. In vivo studies employing chronic rodent myocardial injury model demonstrated that miR‐181a antagomir has a beneficial effect on cardiac function. Subsequently, immunohistochemical and molecular studies suggested that the downregulation of miR‐181a resulted in the attenuation of myocardial fibrosis and hypertrophy, restoring the injured rodent heart after myocardial infarction. Conclusions We demonstrate that an additional mechanism of action of the pleiotropic effects of sacubitril/valsartan may be mediated by the modulation of the mi RNA expression level in the exosome payload.

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Abstract 248: Comparison Of Transplantation Of Bone Marrow-derived Stem Cells, Adipose-derived Stem Cells And Endometrium- Derived Stem Cells In The Infarcted Heart

Circulation Research ◽

10.1161/res.115.suppl_1.248 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Xin Yang Hu ◽

Kan Wang ◽

Jian-an Wang

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Bone Marrow ◽

Flow Cytometry ◽

Adipose Tissue ◽

Cardiac Function ◽

Control Cell ◽

Intramyocardial Injection ◽

Infarcted Heart

Background: A variety of adult stem cells have been transplanted into the infarcted heart to cure myocardial infarction(MI), however, comparative studies are lacking to show more suitable source of cells for transplantation. Mesenchymal stem cells hold promise for myocardial regeneration therapy. Derivation of these cells from the endometrium tissue might be easier compared to bone marrow and adipose tissue. However,the in vivo fate of endometrium stem cells (EnSCs) in the infarcted heart has never been compared directly to mesenchymal cells derived from bone marrow(BMMSCs) and adipose tissue(AdMSCs). Methods: EnSCs, AdMSCs and BMMSCs were isolated from healthy donors were characterized using flow cytometry for surface markers identification and microscopy for cell morphology. They were characterized with β-actin promoter driving firefly luciferase and green fluorescent protein (Fluc-GFP) double fusion reporter gene, and were characterized using flow cytometry, bioluminescence imaging (BLI) and luminometry. Cell proliferation was tested by CCK-8 kit, colony forming unit(CFU) was stained by crystal violet staining and apoptosis ratio were detected by TUNEL assay. Rat (n=8/group) underwent myocardial infarction followed by intramyocardial injection of 5х105 EnSCs, AdMSCs and BMMSCs, or saline (negative control). Cell survival was measured using BLI for 6 weeks and cardiac function was monitored by echocardiography and hemodynamics analysis. Ventricular morphology was assessed using histology. Results: EnSCs, AdMSCs and BMMSCs were CD29+, CD90+, CD105+, shared similar morphology, but EnSCs had best proliferation, colony-forming and anti-apoptosis activity of 3 types of MSCs. Cells expressed Fluc reporter genes in a number-dependent fashion, as confirmed by luminometry. After cardiac transplantation, transplantation of EnSCs was better capable of preserving ventricular function and dimensions than others, as confirmed by echo test, PV-loops and histology. Conclusions: This is the first study comparing the in in vitro and in vivo behavior of 3 types of MSCs in the infarcted heart. AdMSCs and BMMSCs do not tolerate well in the cardiac environment, resulting in more cell death andworse cardiac function than EnSCs groups.

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