Mohamed Doaa I, Ezzat Samar F, Elayat Wael M, El-Kharashi Omnyah A, El-Kareem Hanaa F Abd, Nahas Hebatallah H Abo, Abdel-Wahab Basel A, Alshawwa Samar Zuhair, Saleh Asmaa, Helmy Yosra A, Khairy Eman, Saied Essa M
Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
Pharmaceuticals (Basel). 2022 Jul 5;15(7):832. doi: 10.3390/ph15070832.
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.
急性心力衰竭（AHF）是老年人群中最常见的可导致死亡的疾病之一。全身低灌注与肝脏缺血再灌注损伤相关，这种损伤可能是不可逆的。AHF所致的缺血性肝炎与肝损伤的发病机制有关。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AHF后缺血性肝损伤中的作用，并探讨了卡维地洛可能的肝脏保护作用。生化分析显示，AHF后的缺血性肝损伤显著提高了丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和碱性磷酸酶（ALP）的活性、总胆红素和直接胆红素水平，以及肝丝裂原活化蛋白激酶（MAPK）、动力蛋白样蛋白1（DNM1L）和肝微小RNA-17的表达。同时，它显著降低了血清白蛋白水平、肝超氧化物歧化酶（SOD）活性，以及线粒体过氧化物酶体增殖物激活受体-1α（PGC-1α）和线粒体融合蛋白2（Mtf2）的表达。肝组织的组织学检查显示肝细胞变性。有趣的是，在异丙肾上腺素诱导的AHF之前或之后给予卡维地洛，生化、免疫组织化学和组织学分析表明，其显著改善了肝功能，并逆转了AHF诱导的缺血性肝炎的恶化作用。我们的数据表明，卡维地洛改善肝脏缺血损伤的肝脏保护作用可能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因子微小RNA-17。为了进一步探索卡维地洛的作用方式，我们通过计算机模拟研究了卡维地洛靶向动力蛋白样蛋白和线粒体动力学蛋白（MID51）的能力。我们的结果显示，卡维地洛对DNM1L蛋白的结合口袋具有高结合亲和力（-14.83千卡/摩尔）。总之，我们的研究突出了卡维地洛在减轻与AHF相关的缺血性肝炎方面的肝脏保护药理学应用。
