病理性心脏重塑与心血管疾病有关,并可导致心力衰竭。核因子-κB(NF-κB)在肥大心脏中上调。此外,G蛋白偶联受体激酶2(GRK2)的表达增加,并与心力衰竭的进展有关。帕罗西汀对GRK2的抑制作用已经确立。然而,其对IκBα/NFκB信号的保护作用尚未阐明。这项研究调查了帕罗西汀在心脏肥大(CH)动物模型中的心脏保护作用。重点研究其对GRK2介导的NF-κB调节的促肥大和促纤维化基因表达的影响。Wistar白化病大鼠给予生理盐水,帕罗西汀,或者氟西汀,其次是异丙肾上腺素诱导CH。通过评估心脏损伤来确定治疗的心脏保护作用。炎症生物标志物水平,组织病理学变化,以及心肌细胞中的肥大和纤维化基因。帕罗西汀预处理显着降低了HW/BW比率(p<0.001),和促肥大和促纤维化基因肌钙蛋白-I的表达(p<0.001),BNP(p<0.01),ANP(p<0.001),羟脯氨酸(p<0.05),TGF-β1(p<0.05),和αSMA(p<0.01)以及炎症标志物。它还显着降低了pIκBα,NFκB(p105)亚基表达(p<0.05)和磷酸化。研究结果表明,帕罗西汀通过抑制GRK2介导的IκBα/NF-κB信号通路来预防病理性心脏重构。
Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (p < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (p < 0.001), BNP (p < 0.01), ANP (p < 0.001), hydroxyproline (p < 0.05), TGF-β1 (p < 0.05), and αSMA (p < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (p < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.