Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Feb;397(2):1151-1162. doi: 10.1007/s00210-023-02680-6. Epub 2023 Aug 26.
Hyperthyroidism is associated with the alteration in molecular pathways involved in the regulation of mitochondrial mass and apoptosis, which contribute to the development of cardiac hypertrophy. Diminazene (DIZE) is an animal anti-infection drug that has shown promising effects on improving cardiovascular disease. The aim of the present study was to investigate the therapeutic effect of DIZE on cardiac hypertrophy and the signaling pathways involved in this process in the hyperthyroid rat model. Twenty male Wistar rats were equally divided into four groups: control, hyperthyroid, DIZE, and hyperthyroid + DIZE. After 28 days of treatment, serum thyroxine (T4) and thyroid stimulating hormone (TSH) level, cardiac hypertrophy indices, cardiac damage markers, cardiac malondialdehyde (MDA), and superoxide dismutase (SOD) level, the mRNA expression level of mitochondrial and apoptotic genes were evaluated. Hyperthyroidism significantly decreased the cardiac expression level of SIRT1/PGC1α and its downstream involved in the regulation of mitochondrial biogenesis, mitophagy, and antioxidant enzyme activities including TFAM, PINK1/MFN2, Drp1, and Nrf2, respectively, as well as stimulated mitochondrial-dependent apoptosis by reducing Bcl-2 expression and increasing Bax expression. Treatment with DIZE significantly reversed the downregulation of SIRT1, PGC1α, PINK1, MFN2, Drp1, and Nrf2 but did not significantly change the TFAM expression. Moreover, DIZE suppressed apoptosis by normalizing the cardiac expression levels of Bax and Bcl-2. DIZE is effective in attenuating hyperthyroidism-induced cardiac hypertrophy by modulating the mitophagy-related pathway, suppressing apoptosis and oxidative stress.
甲状腺功能亢进症与调节线粒体质量和细胞凋亡的分子途径的改变有关，这有助于心脏肥大的发展。苯哒嗪（DIZE）是一种动物抗感染药物，在改善心血管疾病方面显示出良好的效果。本研究旨在探讨 DIZE 对甲状腺功能亢进大鼠模型中心脏肥大及相关信号通路的治疗作用。20 只雄性 Wistar 大鼠等分为 4 组：对照组、甲状腺功能亢进组、DIZE 组和甲状腺功能亢进+DIZE 组。治疗 28 天后，检测血清甲状腺素（T4）和促甲状腺激素（TSH）水平、心脏肥大指数、心脏损伤标志物、心脏丙二醛（MDA）和超氧化物歧化酶（SOD）水平，评估线粒体和凋亡基因的 mRNA 表达水平。甲状腺功能亢进症显著降低了 SIRT1/PGC1α 的心脏表达水平及其下游与线粒体生物发生、线粒体自噬和抗氧化酶活性调节相关的基因，包括 TFAM、PINK1/MFN2、Drp1 和 Nrf2，同时通过降低 Bcl-2 表达和增加 Bax 表达来刺激线粒体依赖性细胞凋亡。DIZE 治疗显著逆转了 SIRT1、PGC1α、PINK1、MFN2、Drp1 和 Nrf2 的下调，但对 TFAM 的表达没有显著影响。此外，DIZE 通过使 Bax 和 Bcl-2 的心脏表达水平正常化来抑制凋亡。DIZE 通过调节自噬相关途径、抑制凋亡和氧化应激，有效减轻甲状腺功能亢进引起的心脏肥大。
