dorsomorphin and Myocardial-Infarction

Because of the minimal and clearly insufficient ability of the adult heart to regenerate after ischemic injury, there is a great opportunity to identify biological mechanisms, substances, and factors that enhance this process. Hence, innovative therapeutic management of heart failure following infarction requires a paradigm shift in pharmacotherapy. Spurred by tremendous progress in the field of stem cell and cardiac biology, several attractive approaches for regeneration of lost cardiomyocytes and supporting vasculature have emerged. Research in this area focuses on restoring the hearts' original function via proliferation and differentiation of cardiac progenitor cells, proliferation of pre-existing cardiomyocytes, and reprogramming of cardiac fibroblasts. In this review, we outline these principal strategies, putative biological targets or signaling pathways and chemical agents, with a focus on small molecules, to achieve therapeutic heart regeneration. We also point out the many remaining questions and challenges, particularly for translating in vitro discoveries to in vivo application.

Topics: Animals; Cell Differentiation; Cell Proliferation; Cellular Reprogramming; Fibroblasts; Humans; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Pluripotent Stem Cells; Regeneration; Signal Transduction; Stem Cells

Diosmetin has shown great potential in the control of several diseases. The aim of the present study was to evaluate the role of diosmetin as a candidate agent for the treatment of myocardial infarction which was mainly caused by hypoxia. The model of hypoxia‑injured myocardial cells was established using the H9c2 cell line. Cell viability was determined using Cell Counting Kit‑8, cell apoptosis was determined by Annexin V‑FITC Apoptosis Detection Kit and cleaved caspase‑3 level was assessed by western blot analysis. Autophagy was monitored using a commercial kit, and a well‑established reporter system was used to confirm the role of diosmetin in autophagy. The activity of adenosine 5'‑monophosphate‑activated protein kinase (AMPK) signaling was detected by western blot analysis. Cell viability assay indicated that diosmetin alleviated hypoxia‑induced cell death of H9c2 cells in a dose‑dependent manner. Data of the apoptosis assay revealed that diosmetin reduced the proportion of apoptotic cells in the hypoxia‑injured H9c2 cells. It was also found that the occurrence of autophagy was promoted when hypoxia‑injured cells were treated with diosmetin alone, and results of the western blot analysis revealed that AMPK signaling was activated by diosmetin. Administration of diosmetin together with an inhibitor of autophagy (3‑methyladenine, 3‑MA) or AMPK (Compound C) was able to decrease the diosmetin‑induced autophagy as well as the cytoprotective effects in the hypoxia‑injured cells. Our study concluded that diosmetin exhibits a cytoprotective effect on hypoxia‑injured myocardial cells by inducing autophagy and alleviating apoptosis. AMPK was demonstrated to regulate the observed effects caused by diosmetin. This investigation confirmed diosmetin as a promising drug candidate for myocardial infarction treatment. The present findings regarding the inherent molecular mechanisms involved in the protective effects of diosmetin promote the clinical application of diosmetin.

Topics: Adenine; Animals; Apoptosis; Autophagy; Cardiovascular Agents; Cell Hypoxia; Cell Line; Cytoprotection; Flavonoids; Mice; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Pyrazoles; Pyrimidines

Transplantation of cardiosphere-derived cells (CDCs) has been shown to exert a therapeutic effect in patients with myocardial infarction (MI). However, poor survival of transplanted CDCs limits their beneficial effect. Metformin (MET) activates AMP-activated protein kinase (AMPK) which is associated with cell survival. The aim of this study is to determine whether MET improves CDC survival in the transplantation microenvironment and enhances the therapeutic effect of CDC transplantation against MI.. CDCs were isolated and expanded from transgenic β-actin-GFP mice. CDCs were pretreated with MET and intramyocardially injected into wild-type C57 mouse heart with MI injury. The survival of CDCs was quantified, and the infarct size and cardiac function of treated hearts were evaluated.. CDC transplantation modestly reduced infarct size and improved cardiac function in the post-MI heart, which was further improved by MET treatment. MET pretreatment significantly increased the survival of CDCs transplanted into the myocardium. MET also reduced CDC apoptosis induced by oxidative stress in vitro. The anti-apoptotic effect of MET was blocked by the AMPK inhibitor compound C. MET increased AMPK phosphorylation and upregulated endothelial nitric oxide synthase (eNOS) in CDCs under oxidative stress, which might be associated with the anti-apoptotic effect of MET.. MET improves the survival of transplanted CDCs in the myocardium, thereby enhancing their therapeutic effect against MI injury. The pro-survival function of MET on CDCs might be associated with an AMPK-eNOS-dependent mechanism.

Topics: AMP-Activated Protein Kinases; Animals; Cell Proliferation; Cell Survival; Fibroblasts; Gene Expression Regulation; Genes, Reporter; Green Fluorescent Proteins; Humans; Hypoglycemic Agents; Injections, Intralesional; Male; Metformin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Phosphorylation; Pyrazoles; Pyrimidines; Spheroids, Cellular

Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-γ agonist, has been demonstrated to possess cardioprotective properties during ischemia-reperfusion. However, this notion remains controversial as recent evidence has suggested an increased risk in cardiac events associated with long-term use of RGZ in patients with type 2 diabetes. In this study, we tested the hypothesis that acute RGZ treatment is beneficial during I/R by modulating cardioprotective signaling pathways in a nondiabetic mouse model. RGZ (1 μg/g) was injected intravenously via the tail vein 5 min before reperfusion. Myocardial infarction was significantly reduced in mice treated with RGZ compared with vehicle controls (8.7% ± 1.1% vs. 20.2% ± 2.5%, P < 0.05). Moreover, isolated hearts were subjected to 20 min of global, no-flow ischemia in an ex vivo heart perfusion system. Postischemic recovery was significantly improved with RGZ treatment administered at the onset of reperfusion compared with vehicle (P < 0.001). Immunoblot analysis data revealed that the levels of both phospho-AMP-activated protein kinase (Thr(172)) and phospho-Akt (Ser(473)) were significantly upregulated when RGZ was administered 5 min before reperfusion compared with vehicle. On the other hand, inflammatory signaling [phospho-JNK (Thr(183)/Tyr(185))] was significantly downregulated as a result of RGZ treatment compared with vehicle (P < 0.05). Intriguingly, pretreatment with the selective PPAR-γ inhibitor GW-9662 (1 μg/g iv) 10 min before reperfusion significantly attenuated these beneficial effects of RGZ on the ischemic heart. Taken together, acute treatment with RGZ can reduce ischemic injury in a nondiabetic mouse heart via modulation of AMP-activated protein kinase, Akt, and JNK signaling pathways, which is dependent on PPAR-γ activation.

Topics: AMP-Activated Protein Kinases; Anilides; Animals; Cardiotonic Agents; Disease Models, Animal; Drug Administration Schedule; Enzyme Activation; Injections, Intravenous; JNK Mitogen-Activated Protein Kinases; Male; Mice; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphorylation; PPAR gamma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Rosiglitazone; Signal Transduction; Thiazolidinediones; Time Factors; Ventricular Function, Left; Ventricular Pressure