Previous studies demonstrated that Bailcalin (BAI) prevented cardiac injuries under different disease models. Whether BAI protected against type 2 diabetes mellitus- (T2DM-) associated cardiomyopathy was investigated in this study. T2DM was established by the combination of streptozotocin injection and high-fat diet in mice. BAI was administered daily for 6 months. After evaluating cardiac functions, mice hearts were removed and processed for morphological, biochemical, and molecular mechanism analyses. Neonatal rat cardiomyocytes (NRCM) were isolated and treated with high glucose and palmitate (HG/Pal) for in vitro investigation. BAI significantly ameliorated T2DM-induced cardiomyocyte hypertrophy, interstitial fibrosis, and lipid accumulation accompanied by markedly improved cardiac functions in diabetic mice. Mechanically, BAI restored decreased phosphorylation of AMPK and enhanced expression and nuclei translocation of Nrf2. In in vitro experiments, BAI also prevented NRCM from HG/Pal-induced apoptosis and oxidative stress injuries by increasing p-AMPK and Nrf2 accumulation. The means by which BAI restored p-AMPK seemed to be related to the antioxidative effects of Nrf2 after silencing AMPK or Nrf2 in NRCM. Furthermore, BAI regulated Nrf2 by inhibiting Nrf2 ubiquitination and consequent degradation mediated by Keap1. This study showed that BAI alleviated diabetes-associated cardiac dysfunction and cardiomyocyte injuries in vivo and in vitro via Keap1/Nrf2/AMPK-mediated antioxidation and lipid-lowering effects. BAI might be a potential adjuvant drug for diabetes cardiomyopathy treatment.

LRRK2 is a Ser/Thr kinase with multiple functional domains. Studies have shown that LRRK2 mutations are closely related to hereditary Parkinson's disease. However, its role in cardiovascular disease, especially in myocardial infarction, is unclear. The aim of this study was to explore the functional role of LRRK2 in myocardial infarction. Wild-type and LRRK2-knockout mice were subjected to coronary artery ligation (left anterior descending) to establish a myocardial infarction model. Neonatal rat cardiomyocytes were subjected to hypoxia to induce hypoxic injury in vitro. We found increased LRRK2 expression levels in the infarct periphery in mouse hearts and hypoxic cardiomyocytes. LRRK2-deficient mice exhibited decreased death rates and reduced infarction areas compared to wild-type controls 14 days after infarction. LRRK2-deficient mice showed reduced left ventricular fibrosis and inflammatory responses, as well as improved cardiac function. In the in vitro study, LRRK2 silencing decreased cleaved caspase-3 activity, reduced cardiomyocyte apoptosis, and diminished hypoxia-induced inflammation. However, LRRK2 overexpression enhanced cleaved caspase-3 activity, increased the number of apoptotic cardiomyocytes, and caused remarkable hypoxia-induced inflammation. When examining the underlying mechanisms, we found that hypoxia increased HIFα expression, which enhanced LRRK2 expression. LRRK2 induced high expression of HMGB1 via P53. When HMGB1 was blocked using an anti-HMGB1 antibody, the deleterious effects caused by LRRK2 overexpression following hypoxia were inhibited in cardiomyocytes. In summary, LRRK2 deficiency protects the heart against myocardial infarction injury. The mechanism underlying this effect involves the P53-HMGB1 pathway.

Doxorubicin- (DOX-) induced cardiomyocyte loss results in irreversible heart failure, which limits the clinical applications of DOX. Currently, there are no drugs that can effectively treat DOX-related cardiotoxicity. Follistatin-like 1 (FSTL1) has been reported to be a transforming growth factor-beta-inducible gene, and FSTL1 supplementation attenuated ischemic injury and cardiac apoptotic loss in mice. However, the effect of FSTL1 on DOX-induced cardiomyopathy has not been elucidated. We aimed to explore whether FSTL1 could prevent DOX-related cardiotoxicity in mice. Mice were intraperitoneally injected with a single dose of DOX to induce acute cardiotoxicity. We used an adeno-associated virus system to overexpress FSTL1 in the heart. DOX administration decreased FSTL1 mRNA and protein expression in the heart and in cells. FSTL1 prevented DOX-related cardiac injury and inhibited cardiac oxidative stress and apoptosis, thereby improving cardiac function in mice. FSTL1 also improved cardiomyocyte contractile functions in vitro. FSTL1 upregulated expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in DOX-treated hearts. FSTL1 was not capable of protecting against these toxic effects in Nrf2-deficient mice. In conclusion, FSTL1 protected against DOX-induced cardiotoxicity via upregulation of Nrf2 expression.

Leucine-rich repetitive kinase-2 (LRRK2) is a Parkinson's disease-related gene that also participates in many inflammatory diseases. However, the functional role of LRRK2 in cardiovascular disease is not clear. In this study, we aimed to elucidate the role of LRRK2 in cardiac remodelling under pressure overload. Aortic banding surgery was performed to induce cardiac remodelling in a LRRK2 knockout mouse model. A cardiomyocyte remodelling model was established by phenylephrine (PE) stimulation in neonatal rat cardiomyocytes. LRRK2 was upregulated in remodelled mouse hearts and cardiomyocytes. Cardiac hypertrophy, fibrosis and dysfunction were ameliorated in LRRK2 knockout mice. LRRK2 silencing protected against the PE-induced cardiomyocyte hypertrophic response, while LRRK2 over-expression worsened the PE-induced hypertrophic response in cardiomyocytes. Decreased autophagy was observed in remodelled cardiomyocytes, whereas LRRK2 silencing increased autophagy levels and LRRK2 overexpression reduced autophagy levels. The autophagy inhibitors 3-MA, bafilomycin and chloroquine reversed the protective effects of LRRK2 deficiency. The autophagy activator rapamycin reversed the deleterious effects of LRRK2 overexpression. We found that LRRK2 inhibited Bcl-2 phosphorylation, thus decreasing the phosphorylation of Beclin1. The protective effects of LRRK2 knockout were partly counteracted by Beclin1(+/−) in vivo and Beclin1 silencing in vitro. We also observed an interaction between LRRK2 and Rab7, an autolysosome degradation-associated protein, which caused Rab7 downregulation. Rab7 knockdown almost completely reversed LRRK2 silencing-induced protection of cardiomyocytes LRRK2 deficiency protected against cardiac remodelling under pressure overload by increasing Bcl-2/Beclin1 and Rab7-regulated autophagy levels in the heart.

The clinical use of doxorubicin (DOX) is largely limited by its cardiotoxicity. Previous studies have shown that jaceosidin has many biological activities. However, little is known about whether jaceosidin can attenuate DOX‐related acute cardiotoxicity. Here, we investigated the therapeutic effects of jaceosidin on DOX‐induced acute cardiotoxicity. Mice were intraperitoneally injected with a single dose of DOX to establish an acute cardiac injury model. To explore the protective effects, mice were orally administered jaceosidin daily for 7 days, with dosing beginning 2 days before DOX injection. The results demonstrated that jaceosidin dose‐dependently reduced free radical generation, inflammation accumulation, and cell loss induced by DOX in cardiomyocytes. Further studies showed that jaceosidin treatment inhibited myocardial oxidative damage and the inflammatory response and attenuated myocardial apoptotic death, thus improving cardiac function in mice injected with DOX. The inhibitory effects of jaceosidin on DOX‐related acute cardiotoxicity were mediated by activation of the sirtuin1 (Sirt1) signaling pathway. Jaceosidin lost its protective effect against DOX‐related injury in Sirt1‐deficient cardiomyocytes and mice. In conclusion, jaceosidin has protective potential in treating DOX‐related cardiac injury through activation of the Sirt1 signaling pathway.

Endothelial‐to‐mesenchymal transition (EndMT) is the process by which endothelial cells lose their endothelial properties and acquire mesenchymal characteristics. Dual‐specific protein phosphatase 22 (DUSP22) inactivates various protein kinases and transcription factors by dephosphorylating serine/threonine residues: hence, it plays a key role in many diseases. The aim of this study was to explore the functional role of DUSP22 in EndMT. In the transforming growth factor‐β‐induced EndMT model in human umbilical vein endothelial cells (HUVECs), we observed a downregulation of DUSP22 expression. This DUSP22 deficiency could aggravate EndMT. Conversely, the overexpression of DUSP22 could ameliorate EndMT. We used signaling pathway inhibitors to verify our results and found that DUSP22 could regulate EndMT through the smad2/3 and the mitogen‐activated protein kinase (MAPK) signaling pathways. In summary, DUSP22 ameliorates EndMT in HUVECs in vitro through the smad2/3 and MAPK signaling pathways.