The Role of Osteopontin-OGDHL Axis in HFpEF

摘要 心力衰竭伴保留射血分数(HFpEF)是一种日益普遍和复杂的综合征 目前尚无病因治疗方法。骨桥蛋白(OPN)是一种诱导线粒体的基质细胞蛋白 心肌细胞的损伤和氧化应激。HFpEF患者循环中OPN表达上调。我们的 工作和初步数据显示，作为肾脏疾病模型的Col4A3-/-小鼠表现出HFpEF表型 这包括心脏舒张期功能障碍、肥大、纤维化、高血压以及肾脏和血浆的升高。 OPN水平。我们的初步数据显示，2-羟基戊二酸脱氢酶的mRNA和蛋白水平- 与OGDHL类似，参与OGDH复合体形成和线粒体能量的Krebs循环同工酶 新陈代谢，在Col4A3-/-心脏中降低。我们发现双基因敲除的Col4A3-/-OPN-/-小鼠 心脏OGDHL蛋白水平，并改善HFpEF表型。HFpEF中的心肌能量学失调 众所周知，患者是疾病进展的主要贡献者。因此，用小动物和大动物 HFpEF模型，我们将检验上调OPN的假设，OPN从肾脏释放出来，激活 心脏中的病理信号导致OGDHL和相关ATP产生的下降 在Col4A3-/-小鼠体内观察HFpEF表型。

SUMMARY Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent and complex syndrome for which no etiological therapy is available. Osteopontin (OPN) is a matricellular protein that induces mitochondrial damage and oxidative stress in cardiac myocytes. OPN is upregulated in the circulation of HFpEF patients. Our work and preliminary data show that the Col4a3-/- mice, a model of kidney disease, display a HFpEF phenotype that includes cardiac diastolic dysfunction, hypertrophy, fibrosis, hypertension, and elevated renal and plasma levels of OPN. Our preliminary data reveals that mRNA and protein levels of 2-Oxoglutarate Dehydrogenase- Like (OGDHL), a Krebs cycle isoenzyme involved in OGDH complex formation and mitochondrial energy metabolism, is decreased in Col4a3-/- hearts. We found that double knockout Col4a3-/-OPN-/- mice have elevated cardiac OGDHL protein levels, and improved HFpEF phenotype. Dysregulated myocardial energetics in HFpEF patients is known to be a major contributor to disease progression. Therefore, using small and large animal models of HFpEF, we will test the hypothesis that upregulated OPN, released from the kidney, activates pathological signaling in the heart causing a decline in OGDHL and related ATP production contributing to the observed HFpEF phenotype in Col4a3-/- mice.