Non-Communicable Disease Group, Translational Health Science and Technology Institute (THSTI), Faridabad 121001, India.
Department of Pharmacology, All India Institute of Medical Science (AIIMS), New Delhi 110029, India.
Oxid Med Cell Longev. 2022 Jun 11;2022:5554290. doi: 10.1155/2022/5554290. eCollection 2022.
Transition from cardiac hypertrophy to failure involves adverse metabolic reprogramming involving mitochondrial dysfunction. We have earlier shown that vitamin D deficiency induces heart failure, at least in part, through insulin resistance. However, whether activation of vitamin D receptor (VDR) can attenuate heart failure and underlying metabolic phenotype requires investigation. Thus, we aimed to assess the cardioprotective potential of paricalcitol, a vitamin D receptor-activator, against cardiac hypertrophy and failure in high-fat high-fructose-fed rats.
Male Sprague Dawley rats were fed control (Con) or high-fat high-fructose (HFHFrD) diet for 20 weeks. After 12 weeks, rats from HFHFrD group were divided into the following: HFHFrD, HFHFrD+P (paricalcitol 0.08 g/kg/day) and HFHFrD+E (enalapril maleate 10 mg/kg/day). Intraperitoneal glucose tolerance test, blood pressure measurement, and 2D echocardiography were performed. Cardiac fibrosis was assessed by Masson's trichrome staining of paraffin-embedded heart sections. Mitochondrial DNA and proteins, and citrate synthase activity were measured in rat hearts. VDR was silenced in H9c2 cardiomyoblasts, and immunoblotting was performed.
Paricalcitol improved glucose tolerance, serum lipid profile, and blood pressure in high-fat high-fructose-fed rats. Paricalcitol reduced cardiac wall thickness and increased ejection fraction in high-fat high-fructose-fed rats but had no effect on perivascular fibrosis. PGC1- was upregulated in the HFHFrD+P group compared to the HFHFrD group, but there was no significant difference in mitochondrial content. Citrate synthase activity was significantly higher in the HFHFrD+P group compared to the HFHFrD group. Rat hearts of the HFHFrD+P group had significantly higher expression of mitofusins. H9c2 cells with VDR knockdown showed significantly lower expression of Mfn2. Improvement in the HFHFrD+P group was comparable with that in the HFHFrD+E group.
Paricalcitol reverses cardiac dysfunction in rats with metabolic syndrome by enhancing mitochondrial fusion. We demonstrate repurposing potential of the drug currently used in end-stage kidney disease.
从心肌肥厚向衰竭的转变涉及到代谢重编程，包括线粒体功能障碍。我们之前已经表明，维生素 D 缺乏会导致心力衰竭，至少部分原因是胰岛素抵抗。然而，维生素 D 受体 (VDR) 的激活是否可以减轻心力衰竭及其潜在的代谢表型仍需要研究。因此，我们旨在评估帕立骨化醇（一种维生素 D 受体激动剂）对高脂肪高果糖喂养大鼠心肌肥厚和衰竭的心脏保护作用。
雄性 Sprague Dawley 大鼠给予对照（Con）或高脂肪高果糖（HFHFrD）饮食 20 周。在 12 周后，HFHFrD 组大鼠分为以下三组：HFHFrD、HFHFrD+P（帕立骨化醇 0.08 g/kg/天）和 HFHFrD+E（马来酸依那普利 10 mg/kg/天）。进行腹腔内葡萄糖耐量试验、血压测量和二维超声心动图检查。通过石蜡包埋心脏切片的 Masson 三色染色评估心肌纤维化。测量大鼠心脏的线粒体 DNA 和蛋白质以及柠檬酸合酶活性。在 H9c2 心肌细胞中沉默 VDR，并进行免疫印迹。
帕立骨化醇改善了高脂肪高果糖喂养大鼠的葡萄糖耐量、血脂谱和血压。帕立骨化醇降低了高脂肪高果糖喂养大鼠的心肌壁厚度并增加了射血分数，但对血管周围纤维化没有影响。与 HFHFrD 组相比，HFHFrD+P 组的 PGC1-上调，但线粒体含量没有差异。与 HFHFrD 组相比，HFHFrD+P 组的柠檬酸合酶活性显著升高。HFHFrD+P 组大鼠心脏的线粒体融合蛋白表达明显更高。沉默 VDR 的 H9c2 细胞的 Mfn2 表达明显降低。HFHFrD+P 组的改善与 HFHFrD+E 组相当。
帕立骨化醇通过增强线粒体融合逆转代谢综合征大鼠的心脏功能障碍。我们证明了目前用于终末期肾病的药物具有重新利用的潜力。
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