The basic pathophysiological mechanisms underlying septic cardiomyopathy have not yet been completely clarified. Disease-specific treatments are lacking, and care is still based on supportive modalities. The aim of our study was to assess the protective effects of melatonin on septic cardiomyopathy, with a focus on the interactions between receptor-interacting protein kinase 3 (Ripk3), the mitochondria, endoplasmic reticulum (ER) and cytoskeletal degradation in cardiomyocytes. Ripk3 expression was increased in heart samples challenged with LPS, followed by myocardial inflammation, cardiac dysfunction, myocardial breakdown and cardiomyocyte death. The melatonin treatment attenuated septic myocardial injury in a comparable manner to the genetic depletion of Ripk3. Molecular investigations revealed that Ripk3 intimately regulated mitochondrial function, ER stress, cytoskeletal homeostasis and cardioprotective signaling pathways. Melatonin-mediated inhibition of Ripk3 improved mitochondrial bioenergetics, reduced mitochondria-initiated oxidative damage, sustained mitochondrial dynamics, ameliorated ER stress, normalized calcium recycling, and activated cardioprotective signaling pathways (including AKT, ERK and AMPK) in cardiomyocytes. Interestingly, Ripk3 overexpression mediated resistance to melatonin therapy following the infection of LPS-treated hearts with an adenovirus expressing Ripk3. Altogether, our findings identify Ripk3 upregulation as a novel risk factor for the development of sepsis-related myocardial injury, and melatonin restores the physiological functions of the mitochondria, ER, contractile cytoskeleton and cardioprotective signaling pathways. Additionally, our data also reveal a new, potentially therapeutic mechanism by which melatonin protects the heart from sepsis-mediated dysfunction, possibly by targeting Ripk3.

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Hypoxia-induced cardiomyocyte apoptosis contributes significantly to the development of numerous cardiac diseases, such as ischemic heart disease, heart failure, etc. Promoting cell survival by inhibiting apoptosis is one of the available strategies to attenuate cardiac dysfunction caused by cardiomyocyte loss. Previous studies have been demonstrated that miR-138 and lipocalin-2 (Lcn2) play important roles in cardiomyocyte apoptosis and survival. We presently determined whether Lcn2 is a target gene of miR-138 involved in hypoxia-induced cardiomyocyte apoptosis. Firstly, mimics of miR-138 were transfected into HL-1 cells to investigate its effect on cell apoptosis. Using 3-(4,5-dimethyl-thiazol-2-y1) 2,5-diphenyl tetrazolium bromide (MTT) and Annexin V-FITC/PI flow cytometer assays, over-expression of miR-138 significantly enhanced the cell growth and significantly attenuated the cell apoptosis in hypoxic conditions. Dual-luciferase reporter gene and western blot results confirmed Lcn2 was a direct target of miR-138. Then, the recombinant plasmid, pcDNA3.1/Lcn2 was transfected into the HL-1 cells that over-expressed miR-138. We further observed that the over-expression of Lcn2 diminished the protection of miR-138 over-expression from hypoxia-induced cell survival and apoptosis. In conclusion, our study demonstrated that up-regulation of miR-138 inhibits the hypoxia-induced cardiomyocyte apoptosis via down-regulating the pro-apoptotic gene expression of Lcn2.

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Background: An increasing number of studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors, initially used as antidiabetic agents, have cardiovascular (CV) benefits. However, few bibliometric analyses have examined this field systematically. Our study aimed to visualize the publications to determine the trends and hotspots in CV research on SGLT2 inhibitors. Methods: Publications on SGLT2 inhibitors in cardiovascular research were retrieved from the Web of Science Core Collection. Microsoft Excel 2019, VOSviewer, and CiteSpace V were used to analyze and plot the references. Results: On July 3, 2020, 1509 records of CV research on SGLT2 inhibitors published from 2013 to 2020 were retrieved. Nearly half were authored by American scholars, and most were published in Diabetes Obesity Metabolism, Cardiovascular Diabetology, and Diabetes Therapy. The USA was the leading driving force, with a strong academic reputation in this area. Inzucchi SE published the most related articles, while Neal B was cited the most frequently. All the top 10 co-cited references were in the leading co-cited journal, The New England Journal of Medicine. "Atherosclerotic cardiovascular event" was the leading research hotspot. The keywords "cardiac metabolism," "heart failure hospitalization," and "heart failure with preserved ejection fraction" appeared most recently as research frontiers. Conclusion: Most studies focused on clinical trial outcomes, such as cardiovascular death and heart failure (HF) hospitalization. The mechanisms of SGLT2 inhibitors, especially those related to cardiac metabolism, may soon become hotspots and should be closely monitored.

BackgroundRestenosis after percutaneous coronary intervention (PCI) is a remained clinical problem which limits long-term success of PCI. Although there was recognition that probucol in treating restenosis after percutaneous transluminal coronary angioplasty, the efficacy of probucol on restenosis after stent-implantation is controversial. So this meta-analysis was conducted to investigate the association between probucol and late restenosis.MethodsArticles were assessed by four trained investigators, with divergences resolved by consensus. PubMed, EMBASE, ScienceDirect and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocated to treatment and a comparison of probucol-treated patients and control patients (not treated with lipid-lowering drug) undergoing PCI.ResultsFifteen studies with 859 subjects were analyzed. Major outcome, binary angiographic restenosis defined as >50% stenosis upon follow-up angiography, was significantly decreased with probucol treatment (RR = 0.59 [0.43, 0.80] among vessels, P = 0.0007; and RR = 0.52 [0.40, 0.68] among patients, P<0.00001). Probucol also increased the minimal luminal diameter (SMD = 0.45 [0.30, 0.61], P<0.00001) and decreased late loss upon follow-up after 6 months (SMD = -0.41 [-0.60, -0.22], P<0.0001). Moreover, there was a significantly lower incidence of major adverse cardiac events (MACE) in the probucol group than control group (RR = 0.69 [0.51, 0.93], P = 0.01).ConclusionProbucol is more than a lipid-lowering drug. It is also effective in reducing the risk of restenosis and incidence of MACE after PCI.

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