Department of Pharmacology and Systems Physiology, University of Cincinnati, OH (C.G., T.L.).
Department of Cardiovascular Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China (Z.X.).
Circ Res. 2024 Aug 16;135(5):614-628. doi: 10.1161/CIRCRESAHA.124.324706. Epub 2024 Jul 16.
Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized.
We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lep/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts.
In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress.
These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.
射血分数保留型心力衰竭（HFpEF）是一种新兴的重大未满足需求，也是心脏病学中最重大的临床挑战之一。HFpEF 的发病机制与多种危险因素有关。高血压和与肥胖相关的代谢紊乱是 HFpEF 患者最突出的两种合并症。尽管高血压引起的机械超负荷长期以来一直被认为是射血分数降低型心力衰竭的一个强有力的致病因素，但机械超负荷与代谢紊乱在 HFpEF 发病机制中的协同相互作用仍未得到很好的描述。
我们通过对瘦 C57Bl/6J 或肥胖/糖尿病 B6.Cg-Lep/J（ob/ob）小鼠进行横主动脉缩窄，应用单细胞核 RNA 测序和靶向调控两个实验组中差异表达的信号通路，研究了心脏同时受到机械和代谢应激的功能结果和潜在机制。
与横主动脉缩窄后的 C57Bl/6J 瘦鼠相比，后者随着时间的推移发展为射血分数降低型心力衰竭的病理特征，横主动脉缩窄后的 ob/ob 鼠的射血分数没有明显变化，但发展出 HFpEF 的特征性病理特征，包括舒张功能障碍、心脏肥大恶化和病理性重构，同时运动耐量进一步恶化。单细胞 RNA 测序分析显示，在压力超负荷和肥胖/糖尿病共同作用下的心肌细胞中，转录组发生了显著的重编程，与单纯受到压力超负荷或肥胖/糖尿病作用的心肌细胞明显不同。此外，胰高血糖素信号被确定为与 HFpEF 相关的心肌细胞中受影响的排名第一的信号通路。用胰高血糖素受体拮抗剂治疗可显著改善 2 种独立的临床前模型中与 HFpEF 相关的病理特征的进展。重要的是，心肌细胞特异性的胰高血糖素受体基因缺失也显著改善了心肌细胞对压力超负荷和代谢应激的反应。
这些发现确定了心肌细胞中的胰高血糖素受体信号是 HFpEF 进展的关键决定因素，并为胰高血糖素受体拮抗作为该疾病的潜在治疗方法提供了概念验证支持。
