Glucose Metabolic Flux Regulates NO And Pathologic Matrices In IPAH Key Words: Pulmonary hypertension, Nitric oxide, O-GlcNAc, Glucose, Hyaluronan, hexosamine Idiopathic Pulmonary arterial Hypertension (IPAH) is a rapidly progressive cardiopulmonary disease with poor prognosis. Presently, IPAH is considered a vasculopathy resulting from morphological changes of the lung vasculature. The molecular underpinnings that cause IPAH have not been determined. In addition, the effectiveness of the present therapies is limited because they do not target specific progressive vascular phenotypes characterized in IPAH. The altered bioavailability of the metabolite nitric oxide (NO) is a hallmark of the disease. Along with NO deficiency, dysregulated glucose metabolism is well described in IPAH. Our long-term goal is to understand how dysregulated glucose uptake/metabolism and NO deficiency promote IPAH with the expectation to design therapeutic treatments and prognostic indicators for the disease. Multiple processes are governed by dysregulated metabolic function in IPAH including cellular proliferation, inflammation, and vascular remodeling. Interestingly, there is also an increase in the extracellular matrix glycosaminoglycan hyaluronan (HA) in IPAH. However, the primary link between (i) dysregulated glucose uptake/metabolism, (ii) NO deficiency and (iii) HA production in IPAH have not been elucidated. More importantly, the molecular mechanisms that trigger and perpetuate these different phenotypes in IPAH remains unclear. The central hypothesis of this proposal is that enhanced HA production and NO deficiency in IPAH result from increased glucose uptake and activation of the hexosamine biosynthetic pathway (HBP). The hypothesis has been formulated based on previously generated preliminary data. Our rationale for the proposed research is designed to establish the effects of increased glucose metabolic flux in IPAH on NO deficiency and HA production and function in order to determine the regulatory role(s) these molecules have in perpetuating primary endothelial and smooth muscle cell proliferation, migration, and vascular remodeling in IPAH. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Investigate the mechanisms whereby metabolic flux regulates NO deficiency, vascular proliferation and remodeling in IPAH;and 2) Determine the regulatory mechanisms associated with the abnormalities in hexosamine biosynthesis and HA production. The proposed research is significant, because it will advance our understanding of the functional role of the HBP as a glucose cellular sensor, regulator of NO production, and facilitator of lung pathological matrices in IPAH. Ultimately, the proposed work will shed light on the important role of the HBP in the regulation of the lung microenvironment in the pathobiology of IPAH and identify potential targets for therapy.

Public Health Relevance

The proposed research is relevant to public health because, to date, there are no straightforward treatments available for pulmonary arterial hypertension, a deadly disease that affects young (predominantly female) individuals. Our proposed work will help design treatment strategies for the disease and is relevant to the NHLBI's mission to promote the prevention and treatment of cardiopulmonary diseases and enhance human life and well-being.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Colombini-Hatch, Sandra
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Heresi, Gustavo A; Malin, Steven K; Barnes, Jarrod W et al. (2017) Abnormal Glucose Metabolism and High-Energy Expenditure in Idiopathic Pulmonary Arterial Hypertension. Ann Am Thorac Soc 14:190-199
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