Although the treatment of myocardial infarction (MI) has improved considerably, it is still a worldwide disease with high morbidity and high mortality. Whilst there is still a long way to go for discovering ideal treatments, therapeutic strategies committed to cardioprotection and cardiac repair following cardiac ischemia are emerging. Evidence of pathological characteristics in MI illustrates cell signaling pathways that participate in the survival, proliferation, apoptosis, autophagy of cardiomyocytes, endothelial cells, fibroblasts, monocytes, and stem cells. These signaling pathways include the key players in inflammation response, e.g., NLRP3/caspase-1 and TLR4/MyD88/NF-κB; the crucial mediators in oxidative stress and apoptosis, for instance, Notch, Hippo/YAP, RhoA/ROCK, Nrf2/HO-1, and Sonic hedgehog; the controller of myocardial fibrosis such as TGF-β/SMADs and Wnt/β-catenin; and the main regulator of angiogenesis, PI3K/Akt, MAPK, JAK/STAT, Sonic hedgehog, etc. Since signaling pathways play an important role in administering the process of MI, aiming at targeting these aberrant signaling pathways and improving the pathological manifestations in MI is indispensable and promising. Hence, drug therapy, gene therapy, protein therapy, cell therapy, and exosome therapy have been emerging and are known as novel therapies. In this review, we summarize the therapeutic strategies for MI by regulating these associated pathways, which contribute to inhibiting cardiomyocytes death, attenuating inflammation, enhancing angiogenesis, etc. so as to repair and re-functionalize damaged hearts. 

https://www.nature.com/articles/s41392-022-00925-z.pdf

Signaling pathways and targeted therapy for myocardial infarction

Stem cell homing is a multistep endogenous physiologic process that is also used by exogenously administered hematopoietic stem and progenitor cells (HSPCs). This multistep process involves cell migration and is essential for hematopoietic stem cell transplantation. The process can be manipulated to enhance ultimate engraftment potential, and understanding stem cell homing is also important to the understanding of stem cell mobilization. Homing is also of potential importance in the recruitment of marrow mesenchymal stem and stromal cells (MSCs) to sites of injury and regeneration. This process is less understood but assumes importance when these cells are used for repair purposes. In this review, the process of HSPC and MSC homing is examined, as are methods to enhance this process.

Stem cell homing: From physiology to therapeutics.

Renal ischemia/reperfusion (I/R) injury is the main reason for acute kidney injury (AKI) and is closely related to high morbidity and mortality. In this study, we found that exosomes from human-bone-marrow-derived mesenchymal stem cells (hBMSC-Exos) play a protective role in hypoxia/reoxygenation (H/R) injury. hBMSC-Exos were enriched in miR-199a-3p, and hBMSC-Exo treatment increased the expression level of miR-199a-3p in renal cells. We further explored the function of miR-199a-3p on H/R injury. miR-199a-3p was knocked down in hBMSCs with a miR-199a-3p inhibitor. HK-2 cells cocultured with miR-199a-3p-knockdown hBMSCs were more susceptible to H/R injury and showed more apoptosis than those cocultured with hBMSCs or miR-199a-3p-overexpressing hBMSCs. Meanwhile, we found that HK-2 cells exposed to H/R treatment incubated with hBMSC-Exos decreased semaphorin 3A (Sema3A) and activated the protein kinase B (AKT) and extracellular-signal-regulated kinase (ERK) pathways. However, HK-2 cells cocultured with miR-199a-3p-knockdown hBMSCs restored Sema3A expression and blocked the activation of the AKT and ERK pathways. Moreover, knocking down Sema3A could reactivate the AKT and ERK pathways suppressed by a miR-199a-3p inhibitor. In vivo, we injected hBMSC-Exos into mice suffering from I/R injury; this treatment induced functional recovery and histologic protection and reduced cleaved caspase-3 and Sema3A expression levels, as shown by immunohistochemistry. On the whole, this study demonstrated an antiapoptotic effect of hBMSC-Exos, which protected against I/R injury, via delivering miR-199a-3p to renal cells, downregulating Sema3A expression and thereby activating the AKT and ERK pathways. These findings reveal a novel mechanism of AKI treated with hBMSC-Exos and provide a therapeutic method for kidney diseases.

Exosomes from human-bone-marrow-derived mesenchymal stem cells protect against renal ischemia/reperfusion injury via transferring miR-199a-3p.

Since online publication of this article, the authors noticed that an incorrect image was used during the compilation of Fig. 2a, which was caused during manuscript preparation. The correct Fig. 2a is shown below.

/pdf/exosomal-mir-25-3p-from-mesenchymal-stem-cells-alleviates-4lcqib8ojl.pdf

Exosomal miR-25-3p from mesenchymal stem cells alleviates myocardial infarction by targeting pro-apoptotic proteins and EZH2.

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) (iPSC-CMs) are a promising cell source for myocardial regeneration, disease modeling and drug assessment. However, iPSC-CMs exhibit immature fetal CM-like characteristics that are different from adult CMs in several aspects, including cellular structure and metabolism. As an example, glycolysis is a major energy source for immature CMs. As CMs mature, the mitochondrial oxidative capacity increases, with fatty acid β-oxidation becoming a key energy source to meet the heart’s high energy demand. The immaturity of iPSC-CMs thereby limits their applications. The aim of this study was to investigate whether the energy substrate fatty acid-treated iPSC-CMs exhibit adult CM-like metabolic properties. After 20 days of differentiation from human iPSCs, iPSC-CMs were sequentially cultured with CM purification medium (lactate+/glucose-) for 7 days and maturation medium (fatty acids+/glucose-) for 3–7 days by mimicking the adult CM’s preference of utilizing fatty acids as a major metabolic substrate. The purity and maturity of iPSC-CMs were characterized via the analysis of: (1) Expression of CM-specific markers (e.g., troponin T, and sodium and potassium channels) using RT-qPCR, Western blot or immunofluorescence staining and electron microscopy imaging; and (2) cell energy metabolic profiles using the XF96 Extracellular Flux Analyzer. iPSCs-CMs (98% purity) cultured in maturation medium exhibited enhanced elongation, increased mitochondrial numbers with more aligned Z-lines, and increased expression of matured CM-related genes, suggesting that fatty acid-contained medium promotes iPSC-CMs to undergo maturation. In addition, the oxygen consumption rate (OCR) linked to basal respiration, ATP production, and maximal respiration and spare respiratory capacity (representing mitochondrial function) was increased in matured iPSC-CMs. Mature iPSC-CMs also displayed a larger change in basal and maximum respirations due to the utilization of exogenous fatty acids (palmitate) compared with non-matured control iPSC-CMs. Etomoxir (a carnitine palmitoyltransferase 1 inhibitor) but not 2-deoxyglucose (an inhibitor of glycolysis) abolished the palmitate pretreatment-mediated OCR increases in mature iPSC-CMs. Collectively, our data demonstrate for the first time that fatty acid treatment promotes metabolic maturation of iPSC-CMs (as evidenced by enhanced mitochondrial oxidative function and strong capacity of utilizing fatty acids as energy source). These matured iPSC-CMs might be a promising human CM source for broad biomedical application.

Fatty Acid-Treated Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes Exhibit Adult Cardiomyocyte-Like Energy Metabolism Phenotypes

Myocardial infarction (MI) results in dysfunction and irreversible loss of cardiomyocytes and is among the most serious health threats today. Bone marrow mesenchymal stem cells (BMSCs), with their capacity for multidirectional differentiation, low immunogenicity, and high portability, can serve as ideal seed cells in cardiovascular disease therapy. In this review, we examine recent literature concerning the application of BMSCs for the treatment of MI and consider the following aspects: activity of transplanted cells, migration and homing of BMSCs, immunomodulatory and anti-inflammatory effects of BMSCs, anti-fibrotic activity of BMSCs, the role of BMSCs in angiogenesis, and differentiation of BMSCs into cardiomyocyte-like cells and endothelial cells. Each aspect is complementary to the others and together they promote the repair of cardiomyocytes by BMSCs after MI. Although transplantation of BMSCs has enabled new options for MI treatment, the critical issue we must now address is the reduced viability of transplanted BMSCs due to inadequate blood supply, poor nourishment of cells, and generation of free radicals. More clinical trials are needed to prove the therapeutic potential of BMSCs in MI.

/pdf/a-brief-review-the-therapeutic-potential-of-bone-marrow-56hq7ecuuc.pdf

A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction.

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) is the principal enzyme involved in alcohol metabolism in humans Emerging evidence has shown that the common rs671 G>A (Glu504Lys) polymorphism in the ALDH2 gene might play a critical role in increasing the susceptibility to coronary heart disease (CHD), including myocardial infarction (MI); however, individually published studies showed inconclusive results This meta-analysis aimed to derive a more precise estimation of the relationship between the ALDH2 rs671 polymorphism and its influence on the susceptibility to CHD and MI Nine case-control studies were included with a total of 7358 subjects, including 1961 CHD patients, 1040 MI patients, and 4357 healthy controls Our meta-analysis results showed that the A variant of the ALDH2 rs671 polymorphism may be associated with increase risks of CHD (odds ratios [OR]=136, 95% confidence interval [CI]=106-175, p=0017) and MI (OR=164, 95% CI=122-220, p=0001) Univariate and multivariate meta-regression analyses showed no potential factors explained heterogeneity No publication bias was detected in this meta-analysis In conclusion, the current meta-analysis indicates that the A variant of the ALDH2 rs671 polymorphism may increase the risk of both CHD and MI among Asian populations

ALDH2 rs671 Polymorphism and Coronary Heart Disease Risk Among Asian Populations: A Meta-Analysis and Meta-Regression

Objective This meta-analysis aims to evaluate the relationships between seven functional polymorphisms in the CETP gene and myocardial infarction (MI) risk. Method The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before March 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Results Nine case-control studies with a total 8,623 MI cases and 8,564 healthy subjects met the inclusion criteria. The results of our meta-analysis suggested that CETP rs708272 (C>T) polymorphism might be correlated with an increased risk of MI, especially among Caucasians. Furthermore, we observed that CETP rs1800775 (C>A) polymorphism might increase the risk of MI. Nevertheless, no similar findings were found for CETP rs5882 (A>G), rs2303790 (A>G), rs1800776 (C>A), rs12149545 (G>A), and rs4783961 (G>A) polymorphisms. Conclusion The current meta-analysis suggests that CETP rs708272 (C>T) and rs1800775 (C>A) polymorphisms may contribute to MI susceptibility, especially among Caucasians. Thus, CETP rs708272 and rs1800775 polymorphisms may be promising and potential biomarkers for early diagnosis of MI.

/pdf/seven-functional-polymorphisms-in-the-cetp-gene-and-4slzhh3udc.pdf

Seven functional polymorphisms in the CETP gene and myocardial infarction risk: a meta-analysis and meta-regression.

ATP binding cassette transporter 1 (ABCB1) plays a critical role in the development and progression of cardiovascular disease. Emerging evidence suggests that common functional polymorphisms in the ABCB1 gene might have an impact on an individual's susceptibility to ischemic heart disease, but individually published results are inconclusive. The MEDLINE (1966–2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980–2013), CINAHL (1982–2013), Web of Science (1945–2013), and the Chinese Biomedical Database (CBM; 1982–2013) were searched without language restrictions. Meta-analysis was performed with the use of the STATA statistical software. Odds ratios (OR) with their 95% confidence intervals (95% CIs) were calculated. Seven case–control studies with a total of 2310 myocardial infarction (MI) patients and 10,506 acute coronary syndrome (ACS) patients met the inclusion criteria. Our meta-analysis results indicated that ABCB1 C3435T polymorphism may be associated with an increased risk of MI and A...

ABCB1 C3435T Polymorphism and the Risk of Ischemic Heart Disease: A Meta-Analysis

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A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction.

ALDH2 rs671 Polymorphism and Coronary Heart Disease Risk Among Asian Populations: A Meta-Analysis and Meta-Regression

Seven functional polymorphisms in the CETP gene and myocardial infarction risk: a meta-analysis and meta-regression.

ABCB1 C3435T Polymorphism and the Risk of Ischemic Heart Disease: A Meta-Analysis