Srinivas Balaji, Fortuno Paula, Peng Hongmei, Xu Jiang, Suhail Hamid, Sabbah Hani N, Rhaleb Nour-Eddine, Matrougui Khalid
Department of Physiological Sciences, EVMS, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA, 23501, USA.
Department of Physiology, School of Medicine, Wayne State University, Detroit, MI, 48202, USA.
Cardiovasc Diabetol. 2025 Jun 13;24(1):250. doi: 10.1186/s12933-025-02703-x.
Heart failure with preserved ejection fraction (HFpEF) is a multifactorial cardiovascular disorder characterized by diastolic dysfunction and often associated with hypertension and metabolic disturbances. We aimed to determine the inter-relationship between C/EBP homologous protein (CHOP) in b-cells and HFpEF development.
Eight-week-old male mice b-cell and b-cell were randomly divided into four groups: control b-cell and b-cell mice subjected to standard diet and water. b -cell and b-cell mice fed a high-fat diet (HFD) and L-NAME (0.5 g/L) for five weeks. A comprehensive cardiovascular, metabolic, and histological evaluation was conducted.
Following five weeks of HFD and L-NAME, b-cell mice exhibited clinical and molecular manifestations of HFpEF. These include diastolic dysfunction, a normal cardiac ejection fraction, hypertension, metabolic disorders, cardiac hypertrophy with fibrosis, pulmonary edema, renal injury, and reduced exercise tolerance. Vascular endothelial dysfunction was also observed. Western blot analysis showed a reduced phosphorylated endothelial nitric oxide synthase in mesenteric resistance arteries (MRA), concomitant with qRT-PCR data revealing elevated inflammatory and unfolded protein response markers in MRA, heart, and pancreas. Interestingly, b-cell mice subjected to an HFD and L-NAME were protected from HFpEF and its associated pathologies. These mice displayed improved cardiac and vascular endothelial function, exercise tolerance, and reduced unfolded protein response and inflammatory factors compared to their b-cell.
Our research indicates that deleting the unfolded protein response CHOP in b-cells has a robust cardiovascular protective effect against HFpEF pathogenesis. Therefore, targeting CHOP in b-cells is a promising lead for HFpEF pathogenesis therapy.
射血分数保留的心力衰竭（HFpEF）是一种多因素心血管疾病，其特征为舒张功能障碍，常与高血压和代谢紊乱相关。我们旨在确定β细胞中C/EBP同源蛋白（CHOP）与HFpEF发展之间的相互关系。
将8周龄雄性小鼠的β细胞随机分为四组：对照组β细胞小鼠给予标准饮食和水。β细胞小鼠喂食高脂饮食（HFD）并饮用含L-NAME（0.5 g/L）的水，持续五周。进行了全面的心血管、代谢和组织学评估。
在HFD和L-NAME处理五周后，β细胞小鼠表现出HFpEF的临床和分子表现。这些表现包括舒张功能障碍、正常的心输出分数、高血压、代谢紊乱、伴有纤维化的心肌肥厚、肺水肿、肾损伤以及运动耐力下降。还观察到血管内皮功能障碍。蛋白质免疫印迹分析显示肠系膜阻力动脉（MRA）中磷酸化内皮型一氧化氮合酶减少，同时定量逆转录聚合酶链反应数据显示MRA、心脏和胰腺中炎症和未折叠蛋白反应标志物升高。有趣的是，接受HFD和L-NAME处理的β细胞小鼠免受HFpEF及其相关病理影响。与它们的β细胞相比，这些小鼠的心脏和血管内皮功能、运动耐力得到改善，未折叠蛋白反应和炎症因子减少。
我们的研究表明，在β细胞中删除未折叠蛋白反应CHOP对HFpEF发病机制具有强大的心血管保护作用。因此，针对β细胞中的CHOP是HFpEF发病机制治疗的一个有前景的线索。
