Department of Cardiology, The First Hospital of Changsha (The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University), Changsha 410005, Hunan Province, PR China.
Department of Gastroenterology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410024, Hunan Province, PR China.
Int Immunopharmacol. 2024 Nov 15;141:112778. doi: 10.1016/j.intimp.2024.112778. Epub 2024 Aug 21.
Renal denervation (RDN) has been proved to relieve cardiac hypertrophy; however, its detailed mechanisms remain obscure. This study investigated the detailed protective mechanisms of RDN against cardiac hypertrophy during hypertensive heart failure (HF).
Male 5-month-old spontaneously hypertension (SHR) rats were used in a HF rat model, and male Wistar-Kyoto (WKY) rats of the same age were used as the baseline control. Myocardial hypertrophy and fibrosis were evaluated by hematoxylin-eosin (HE) staining and Masson staining. The expression of target molecule was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, immunohistochemical and immunofluorescence, respectively. Cardiomyocyte hypertrophy was induced by norepinephrine (NE) in H9c2 cells in vitro and evaluated by brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), β-myosin heavy chain (β-MHC), and α-myosin heavy chain (α-MHC) levels. Oxidative stress was determined by malondialdehyde (MDA) level, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) enzyme activities. Mitochondrial function was measured by mitochondrial membrane potential, adenosine triphosphate (ATP) production, mitochondrial DNA (mtDNA) number, and mitochondrial complex I-IV activities. Molecular mechanism was assessed by dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays.
RDN decreased sympathetic nerve activity, attenuated myocardial hypertrophy and fibrosis, and improved cardiac function in the rat model of HF. In addition, RDN ameliorated mitochondrial oxidative stress in myocardial tissues as evidenced by reducing MDA and mitochondrial reactive oxygen species (ROS) levels, and enhancing SOD and GSH-Px activities. Moreover, phosphofurin acid cluster sorting protein 2 (PACS-2) and broad-complex, tramtrak and bric à brac (BTB) domain and cap'n'collar (CNC) homolog 1 (BACH1) were down-regulated by RDN. In NE-stimulated H9c2 cells, PACS-2 and BACH1 levels were markedly elevated, and knockdown of them could suppress NE-induced oxidative stress, cardiomyocyte hypertrophy, fibrosis, as well as mitochondrial dysfunction. Transforming growth factor beta1(TGFβ1)/SMADs signaling pathway was inactivated by RDN in the HF rats, which sequentially inhibited specificity protein 1 (SP1)-mediated transcription of PACS2 and BACH1.
Collectively, these data demonstrated that RDN improved cardiac hypertrophy and sympathetic nerve activity of HF rats via repressing BACH1 and PACS-2-mediated mitochondrial oxidative stress by inactivating TGF-β1/SMADs/SP1 pathway, which shed lights on the cardioprotective mechanism of RDN in HF.
肾去神经术（RDN）已被证明可减轻心脏肥大；然而，其详细的机制仍不清楚。本研究探讨了 RDN 在高血压性心力衰竭（HF）期间对抗心脏肥大的详细保护机制。
雄性 5 月龄自发性高血压（SHR）大鼠用于 HF 大鼠模型，同年龄雄性 Wistar-Kyoto（WKY）大鼠用作基线对照。通过苏木精-伊红（HE）染色和 Masson 染色评估心肌肥大和纤维化。通过逆转录定量聚合酶链反应（RT-qPCR）、Western blot、免疫组织化学和免疫荧光分别分析靶分子的表达。体外使用去甲肾上腺素（NE）诱导 H9c2 细胞心肌肥大，并通过脑钠肽（BNP）、心钠肽（ANP）、β-肌球蛋白重链（β-MHC）和α-肌球蛋白重链（α-MHC）水平评估。通过丙二醛（MDA）水平、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）酶活性测定氧化应激。通过测量线粒体膜电位、三磷酸腺苷（ATP）产生、线粒体 DNA（mtDNA）数量和线粒体复合物 I-IV 活性来评估线粒体功能。通过双荧光素酶报告基因和染色质免疫沉淀（ChIP）实验评估分子机制。
RDN 降低了交感神经活性，减轻了 HF 大鼠模型中的心肌肥大和纤维化，并改善了心脏功能。此外，RDN 改善了心肌组织中的线粒体氧化应激，表现为 MDA 和线粒体活性氧（ROS）水平降低，SOD 和 GSH-Px 活性增强。此外，磷酸化纤维蛋白酸性簇分选蛋白 2（PACS-2）和广泛复杂、tramtrak 和 bric-à-brac（BTB）域和 cap'n'collar（CNC）同源物 1（BACH1）被 RDN 下调。在 NE 刺激的 H9c2 细胞中，PACS-2 和 BACH1 水平显著升高，敲低它们可抑制 NE 诱导的氧化应激、心肌肥大、纤维化和线粒体功能障碍。HF 大鼠中 RDN 使转化生长因子β1（TGFβ1）/SMADs 信号通路失活，从而依次抑制特异性蛋白 1（SP1）介导的 PACS2 和 BACH1 的转录。
综上所述，这些数据表明，RDN 通过抑制 BACH1 和 PACS-2 介导的线粒体氧化应激，通过使 TGF-β1/SMADs/SP1 通路失活来改善 HF 大鼠的心脏肥大和交感神经活性，这为 RDN 在 HF 中的心脏保护机制提供了新的认识。
