Abstract：
Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia-reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (-14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.
摘要：
急性心力衰竭（AHF）是老年最常见的疾病之一，可导致死亡。全身性低灌注与肝脏缺血再灌注损伤有关,这可能是不可逆转的。由AHF引起的缺血性肝炎与肝损伤的发病机理有关。在本研究中,我们广泛研究了线粒体动力学相关蛋白及其表观遗传调控在急性心力衰竭后缺血性肝损伤中的作用,并探讨了卡维地洛可能的保肝作用.生化分析表明，AHF后的缺血性肝损伤显着升高丙氨酸转氨酶（ALT）的活性，天冬氨酸转氨酶（AST），和碱性磷酸酶（ALP）酶，总胆红素和直接胆红素的水平，和肝有丝分裂原活化蛋白激酶（MAPK）的表达，dynamin-1-likeprotein(DNM1L),和肝脏miRNA-17。同时,它显著降低了血清白蛋白水平，肝超氧化物歧化酶（SOD）的活性，线粒体过氧化物酶体增殖物激活受体-1α（PGC-1α）的表达，和mitofusin2（Mtf2）。肝组织的组织学检查显示退化的肝细胞。有趣的是,在异丙肾上腺素诱导的AHF之前或之后施用卡维地洛显著改善了肝功能并逆转了AHF诱导的缺血性肝炎的恶化效应，正如生物化学所证明的那样，免疫组织化学，和组织学分析。我们的结果表明，卡维地洛在改善肝缺血损伤中的肝保护作用可归因于其靶向线粒体动力学相关蛋白（Mtf2，DNM1L和PGC-1α）的能力，以及它们的表观遗传调节子miRNA-17。为了进一步探索卡维地洛的作用模式，我们已经调查过了,在硅，卡维地洛靶向dynamin-1-like蛋白和线粒体动力学蛋白（MID51）的能力。我们的结果表明，卡维地洛对DNM1L蛋白的结合袋具有很高的结合亲和力（-14.83kcal/mol）。总之,我们的研究强调了卡维地洛在减轻与AHF相关的缺血性肝炎中的保肝药理应用。
