BACKGROUND: Ischemic heart diseases (IHD), characterized by metabolic dysregulation, contributes majorly to the global morbidity and mortality. Glucose, lipid and amino acid metabolism are critical energy production for cardiomyocytes, and disturbances of these metabolism lead to the cardiac injury. Traditional Chinese medicine (TCM), widely used for treating IHD, have been demonstrated to effectively and safely regulate the cardiac metabolism reprogramming.
OBJECTIVE: This study discussed and analyzed the disturbed cardiac metabolism induced by IHD and development of formulas, extracts, single herb, bioactive compounds of TCM ameliorating IHD injury via metabolism regulation, with the aim of providing a basis for the development of clinical application of therapeutic strategies for TCM in IHD.
METHODS: With \"ischemic heart disease\", \"myocardial infarction\", \"myocardial ischemia\", \"metabolomics\", \"Chinese medicine\", \"herb\", \"extracts\" \"medicinal plants\", \"glucose\", \"lipid metabolism\", \"amino acid\" as the main keywords, PubMed, Web of Science, and other online search engines were used for literature retrieval.
RESULTS: IHD exhibits a close association with metabolism disorders, including but not limited to glycolysis, the TCA cycle, oxidative phosphorylation, branched-chain amino acids, fatty acid β-oxidation, ketone body metabolism, sphingolipid and glycerol-phospholipid metabolism. The therapeutic potential of TCM lies in its ability to regulate these disturbed cardiac metabolisms. Additionally, the active ingredients of TCM have depicted wonderful effects in cardiac metabolism reprogramming in IHD.
CONCLUSIONS: Drawing from the principles of TCM, we have pinpointed specific herbal remedies for the treatment of IHD, and leveraged advanced metabolomics technologies to uncover the effect of these TCMs on metabolomics alteration. In the future, further clinical experimental studies should be included to explore whether more TCM medicines can play a therapeutic role in IHD by reversing cardiac metabolism disorders; multi-omics would be conducted to explore more pathways and genes targeting such metabolism reprogramming by TCMs, and to seek more TCM therapies for IHD.

Extracellular vesicles (EVs) derived from various cell sources exert cardioprotective effects during cardiac ischemic injury. Our previous study confirmed that EVs derived from ischemic-reperfusion injured heart tissue aggravated cardiac inflammation and dysfunction. However, the role of EVs derived from normal cardiac tissue in myocardial ischemic injury remains elusive.
In the present study, normal heart-derived EVs (cEVs) and kidney-derived EVs (nEVs) were isolated and intramyocardially injected into mice after myocardial infarction (MI). We demonstrated that administration of both cEVs and nEVs significantly improved cardiac function, reduced the scar size, and alleviated inflammatory infiltration into the heart. In addition, cardiomyocyte apoptosis was inhibited, whereas angiogenesis was enhanced in the hearts receiving cEVs or nEVs treatment. Moreover, intramyocardial injection of cEVs displayed much better cardiac protective efficacy than nEVs in murine MI models. RNA-seq and protein-protein interaction (PPI) network analysis revealed the protective mRNA clusters in both cEVs and nEVs. These mRNAs were involved in multiple signaling pathways, which may synergistically orchestrate to prevent the heart from further damage post MI.
Collectively, our results indicated that EVs derived from normal heart tissue may represent a promising strategy for cardiac protection in ischemic heart diseases.

Ischemic heart diseases remain the leading cause of death globally, and stem cell-based therapy has been investigated as a potential approach for cardiac repair. Due to poor survival and engraftment in the cardiac ischemic milieu post transplantation, the predominant therapeutic effects of stem cells act via paracrine actions, by secreting extracellular vesicles (EVs) and/or other factors. Exosomes are nano-sized EVs of endosomal origin, and now viewed as a major contributor in facilitating myocardial repair and regeneration. However, EV/exosome therapy has major obstacles before entering clinical settings, such as limited production yield, unstable biological activity, poor homing efficiency, and low tissue retention. This review aims to provide an overview of the biogenesis and mechanisms of stem cell-derived EV/exosomes in the process of cardiac repair and discuss the current advancements in different optimized strategies to produce high-yield EV/exosomes with higher bioactivity, or engineer them with improved homing efficiency and therapeutic potency. In particular, we outline recent findings toward preclinical and clinical translation of EV/exosome therapy in ischemic heart diseases, and discuss the potential barriers in regard to clinical translation of EV/exosome therapy.

BACKGROUND: The field of network pharmacology showed significant development. The concept of network pharmacology has many similarities to the philosophy of traditional Chinese medicine (TCM), making it suitable to understand the action mechanisms of TCM in treating complex diseases, such as ischemic heart diseases (IHDs).
OBJECTIVE: This review summarizes the representative applications of network pharmacology in deciphering the mechanism underlying the treatment of IHDs with TCM.
METHODS: In this report, we used \"ischemic heart disease\" OR \"coronary heart disease\" OR \"coronary artery disease\" OR \"myocardial ischemia\" AND (\"network pharmacology\" OR \"systematic pharmacology\") as keywords to search for publications from PubMed, the Web of Science, and Google Scholar databases and then analyzed the representative research reports that summarized and validated the active components and targets network of TCM in improving IHDs to show the advantages and deficiencies of network pharmacology applied in TCM research.
RESULTS: The network pharmacology research indicated that HGF, PGF, MMP3, INSR, PI3K, MAPK1, SRC, VEGF, VEGFR-1, NO, eNOS, NO3, IL-6, TNF-α, and more are the main targets of TCM. Apigenin, 25S-macrostemonoside P, ginsenosides Re, Rb3, Rg3, SheXiang XinTongNing, colchicine, dried ginger-aconite decoction, Suxiao Xintong dropping pills, Ginseng-Danshen drug pair and Shenlian and more are the active ingredients, extracts, and formulations of TCM to ameliorate IHDs. These active compounds, extract, and formulations of TCM treat IHDs by delaying ventricular remodeling, reducing myocardial fibrosis, decreasing reactive oxygen species, regulating myocardial energy metabolism, ameliorating inflammation, mitigating apoptosis, and many other aspects.
CONCLUSIONS: The network pharmacology supplies a novel research exemplification for understanding the treatment of IHDs with TCM. However, the application of network pharmacology in TCM studies is still at a superficial level. By rational combining artificial intelligence technology and network pharmacology, molecular biology, metabolomics, and other advanced theories and technologies, and systematically studying the metabolic process and the network among products, targets, and pathways of TCM from the clinical perspective may be a potential development trend in network pharmacology.

Coronary collateral growth is a natural bypass for ischemic heart diseases. It offers tremendous therapeutic benefit, but the process of coronary collateral growth isincompletely understood due to limited preclinical murine models that would enable interrogation of its mechanisms and processes via genetic modification and lineage tracing. Understanding the processes by which coronary collaterals develop can unlock new therapeutic strategies for ischemic heart disease.
To develop a murine model of coronary collateral growth by repetitive ischemia and investigate whether capillary endothelial cells could contribute to the coronary collateral formation in an adult mouse heart after repetitive ischemia by lineage tracing.
A murine model of coronary collateral growth was developed using short episodes of repetitive ischemia. Repetitive ischemia stimulation resulted in robust collateral growth in adult mouse hearts, validated by high-resolution micro-computed tomography. Repetitive ischemia-induced collateral formation compensated ischemia caused by occlusion of the left anterior descending artery. Cardiac function improved during ischemia after repetitive ischemia, suggesting the improvement of coronary blood flow. A capillary-specific Cre driver (Apln-CreER) was used for lineage tracing capillary endothelial cells. ROSA mT/mG reporter mice crossed with the Apln-CreER transgene mice underwent a 17 days\' repetitive ischemia protocol for coronary collateral growth. Two-photon and confocal microscopy imaging of heart slices revealed repetitive ischemia-induced coronary collateral growth initiated from sprouting Apelin+ endothelial cells. Newly formed capillaries in the collateral-dependent zone expanded in diameter upon repetitive ischemia stimulation and arterialized with smooth muscle cell recruitment, forming mature coronary arteries. Notably, pre-existing coronary arteries and arterioles were not Apelin+, and all Apelin+ collaterals arose from sprouting capillaries. Cxcr4, Vegfr2, Jag1, Mcp1, and Hif1⍺ mRNA levels in the repetitive ischemia-induced hearts were also upregulated at the early stage of coronary collateral growth, suggesting angiogenic signaling pathways are activated for coronary collaterals formation during repetitive ischemia.
We developed a murine model of coronary collateral growth induced by repetitive ischemia. Our lineage tracing study shows that sprouting endothelial cells contribute to coronary collateral growth in adult mouse hearts. For the first time, sprouting angiogenesis is shown to give rise to mature coronary arteries in response to repetitive ischemia in the adult mouse hearts.

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Cardiac remodeling is a common pathological process in various heart diseases, such as cardiac hypertrophy, diabetes-associated cardiomyopathy and ischemic heart diseases. The inhibition of cardiac remodeling has been suggested to be a potential strategy for preventing heart failure. However, the mechanisms involved in cardiac remodeling are quite complicated. Recent studies have reported a close correlation between autophagy and energy homeostasis in cardiac remodeling associated with various heart diseases. In this review, we summarize the roles of autophagy and energy homeostasis in cardiac remodeling and discuss the relationship between these two processes in different conditions to identify potential targets and strategies for treating cardiac remodeling by regulating autophagy.

UNASSIGNED: MicroRNAs (miRNAs) are considered as crucial modulators in myocardial ischemia and reperfusion (I/R) injury. The present study aimed to investigate the expression and biological functions of miR-214-5p via targeting Fas ligand (FASLG) in I/R injury.
UNASSIGNED: Lactate dehydrogenase, casein kinase, malondialdehyde assay, reactive oxygen species (ROS) detection and cell apoptosis analysis measured cell damage and cell apoptosis in H9c2 cells under hypoxia/reperfusion (H/R) treatment. Bioinformatics and dual luciferase reporter assays demonstrated the molecular mechanism of miR-214-5p in cardiac cells. 2,3,5-Triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining and adenovirus injection were performed in I/R treated mice.
UNASSIGNED: The expression of miR-214-5p was decreased in H/R injured H9c2 cells compared with control cells (p < 0.001). Overexpression of miR-214-5p reduced cell damage and apoptosis in H9c2 cells under H/R treatment (p < 0.001). Further study revealed that FASLG was a target of miR-214-5p. Enhanced expression of FASLG attenuated the protective function of miR-214-5p in H9c2 cells subjected to H/R injury (P < 0.001). Moreover, the elevated expression of miR-214-5p by adenovirus injection protected cardiac cells from I/R injury in mice (n = 6/per group).
UNASSIGNED: We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG in vitro and in vivo.

Adipose-derived stem cells (ASCs) are promising therapeutic cells for ischemic heart diseases, due to the ease and efficiency of acquisition, the potential of myocardial lineage differentiation, and the paracrine effects. Recently, many researchers have claimed that the ASC-based myocardial repair is mainly attributed to its paracrine effects, including the anti-apoptosis, pro-angiogenesis, anti-inflammation effects, and the inhibition of fibrosis, rather than the direct differentiation into cardiovascular lineage cells. However, the usage of ASCs comes with the problems of low cardiac retention and survival after transplantation, like other stem cells, which compromises the effectiveness of the therapy. To overcome these drawbacks, researchers have proposed various strategies for improving survival rate and ensuring sustained paracrine secretion. They also investigated the safety and efficacy of phase I and II clinical trials of ASC-based therapy for cardiovascular diseases. In this review, we will discuss the characterization and paracrine effects of ASCs on myocardial repair, followed by the strategies for stimulating the paracrine secretion of ASCs, and finally their clinical usage.

OBJECTIVE: The sphingolipid metabolite sphingosine 1‑phosphate (S1P) has emerged as a potential cardioprotective molecule against ischemic heart disease. Moreover, S1P triggers mobilization and homing of bone marrow-derived stem/progenitor cells into the damaged heart. However, it remains elusive whether S1P promotes mesenchymal stem cells (MSCs)-mediated cardioprotection against ischemic heart diseases.
METHODS: Adipose tissue-derived MSCs (AT-MSCs) were obtained from GFP transgenic mice or C57BL/6J. Myocardial infarction (MI) was induced in C57BL/6J mice by ligation of the left anterior descending coronary artery (LAD). Subsequently, S1P-treated AT-MSCs or vehicle-treated AT-MSCs were intravenously administered for 24 h after induction of MI or sham procedure.
RESULTS: Pre-conditioning with S1P significantly enhanced the migratory and anti-apoptotic efficacies of AT-MSCs. In MI-induced mice, intravenous administration of S1P-treated AT-MSCs significantly augmented their homing and engraftment in ischemic area. Besides, AT-MSCs with S1P pre-treatment exhibited enhanced potencies to inhibit cardiomyocyte apoptosis and fibrosis, and stimulate angiogenesis and preserve cardiac function. Mechanistic studies revealed that S1P promoted AT-MSCs migration through activation of ERK1/2-MMP-9, and protected AT-MSCs against apoptosis via Akt activation. Further, S1P activated the ERK1/2 and Akt via S1P receptor 2 (S1PR2), but not through S1PR1. S1PR2 knockdown by siRNA, however, significantly attenuated S1P-mediated AT-MSCs migration and anti-apoptosis.
CONCLUSIONS: The findings of the present study revealed the protective efficacies of S1P pretreatment on the survival/retention and cardioprotection of engrafted MSCs. Pre-conditioning of donor MSCs with S1P is an effective strategy to promote the therapeutic potential of MSCs for ischemic heart diseases.