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

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.

Download Full-text

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).

Download Full-text

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

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0206-6 ◽

2019 ◽

Vol 51 (2) ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Sunghun Lee ◽

Dong Hun Lee ◽

Bong-Woo Park ◽

Riyoun Kim ◽

Anh Duc Hoang ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Vascular Regeneration

Download Full-text

Effects of In Vivo Gene Transfer of Fibroblast Growth Factor-2 on Cardiac Function and Collateral Vessel Formation in the Microembolized Rabbit Heart

Japanese Circulation Journal ◽

10.1253/jcj.65.226 ◽

2001 ◽

Vol 65 (3) ◽

pp. 226-231 ◽

Cited By ~ 9

Author(s):

Mitsuo Iwatate ◽

Toshiro Miura ◽

Yasuhiro Ikeda ◽

Shuji Kawamura ◽

Yuka Dairaku ◽

...

Keyword(s):

Growth Factor ◽

Gene Transfer ◽

Cardiac Function ◽

Fibroblast Growth Factor ◽

Rabbit Heart ◽

Fibroblast Growth Factor 2 ◽

Fibroblast Growth ◽

Collateral Vessel ◽

In Vivo Gene Transfer

Download Full-text

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.

Download Full-text