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Impaired mitochondrial fusion in pulmonary arterial hypertension

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This proposal responds to the broad challenge area (04): Clinical Research and specific challenge topic 04-HL-102: Develop Integrative Strategies to Elucidate the Mechanisms of Lung Diseases. Pulmonary arterial hypertension (PAH) is a syndrome characterized by obstructive vascular remodeling, inflammation and vasoconstriction of small pulmonary arteries. Despite recent therapeutic advances, 1-year mortality rates remains high (~15%). Although abnormalities of the platelets, endothelium and adventitia contribute critically to the pathogenesis of PAH, excessive proliferation of pulmonary arterial smooth muscle cells (PASMC) is a major contributor to the obstructive vascular pathology. This challenge proposal explores 2 newly-recognized abnormalities that promote PASMC proliferation. We recently discovered that the mitochondrial network is disrupted in PAH PASMC and noted that this is related to the proliferative diathesis of these cells. Fragmentation of the mitochondrial network appears to reflect impaired mitochondrial fusion and is associated with 2 related abnormalities: 1) normoxic activation of the master hypoxic transcription factor, hypoxia inducible factor (HIF-1a) and 2) downregulation of mitofusin-2. Normally, mitochondria rapidly join and break apart through highly regulated processes called fusion and fission, respectively. The balance of fusion and fission dynamically regulates the integrity of the reticulum. Fusion is regulated by SNARE-like proteins called mitofusin-1 and mitofusin-2. Fusion redistributes mitochondrial proteins/genes, protecting the cell from oxidant stress, apoptosis and mitochondrial DNA mutations. Impaired fusion alters mitochondrial membrane potential, impairs respiration and promotes SMC proliferation. We evaluate the hypothesis that a HIF-1a-mediated mitofusin-2 deficiency promotes PASMC proliferation and contributes to PAH. Relevant to PAH, mitofusin-2 is a brake on SMC proliferation. Indeed, when first cloned, mitofusin-2 was named hyperplasia suppressor gene. Mitofusin-2 gene therapy reduces intimal hyperplasia in a systemic arterial injury model. HIF-1a is known to downregulate mitofusin-2 expression. Impaired fusion and normoxic HIF-1a activation are found in humans with PAH and fawn-hooded rats (FHR), a strain that spontaneously develops PAH.

PUBLIC HEALTH RELEVANCE: We are investigating the mechanism of pulmonary arterial hypertension (PAH) in Fawn Hooded Rats (FHR), and have identified problems in the FHR's mitochondria, namely lower production of hydrogen peroxide and fragmentation of the mitochondrial network, which create a pseudohypoxic environment that favors rapid cell growth and blood vessel blockage. Preliminary studies show that FHR suffer from activation of an hypoxia inducible factor" (HIF-1a) and a related break-up of the mitochondrial network due to a deficiency of mitofusin 2 (which triggers excessive growth of arterial smooth muscle cells and blocks the lung circulation). This proposal seeks to understand the role of the HIF-1a and mitofusin in PAH and develop therapies (inhibition of HIF-1 a and supplementation of mitofusin-2) to restore mitochondrial form and function and cure PAH.

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