The Role of Osteopontin-OGDHL Axis in HFpEF

总结 射血分数保留性心力衰竭（HFpEF）是一种日益普遍和复杂的综合征， 没有可用的病因治疗。骨桥蛋白（OPN）是一种基质细胞蛋白， 损伤和心肌细胞的氧化应激。OPN在HFpEF患者的循环中上调。我们 工作和初步数据显示，Col 4a 3-/-小鼠，一种肾脏疾病模型，显示HFpEF表型 包括心脏舒张功能障碍、肥大、纤维化、高血压和肾和血浆 OPN水平。我们的初步数据表明，2-酮戊二酸脱氢酶的mRNA和蛋白水平， 类似（OGDHL），一种参与OGDH复合物形成和线粒体能量的克雷布斯循环同工酶 在Col 4a 3-/-心脏中代谢减少。我们发现，双敲除Col 4a 3-/-OPN-/-小鼠具有升高的 心脏OGDHL蛋白水平，并改善HFpEF表型。HFpEF中的心肌能量失调 已知患者是疾病进展的主要贡献者。因此，使用小型和大型动物 在HFpEF模型中，我们将检验从肾脏释放的上调的OPN激活HFpEF的假设。 心脏中的病理信号传导导致OGDHL和相关ATP产生的下降， 在Col 4a 3-/-小鼠中观察到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.