Numerous epidemiological studies showed that people who live in cold regions have a higher incidence of pulmonary and cardiovascular diseases (see Background). In the US, the highest mortality and morbidity due to pulmonary and cardiovascular diseases occur in the cold winter season. Cold temperatures increase the severity of pulmonary and cardiovascular diseases. Our long-term goal is to understand cold temperatures as a risk factor for cardiovascular dysfunction for developing preventive and therapeutic strategies. Intermittent exposure to moderate cold (5?C) causes pulmonary vascular inflammation and dysfunction, pulmonary arterial hypertension and right ventricular (RV) hypertrophy in rats, namely cold-induced pulmonary hypertension (CIPH). The characteristics of animal CIPH (high pulmonary arterial pressure, pulmonary artery hypertrophy, plexiform lesion) mimic those of human idiopathic PH, making it a relevant and unique model for studying PH. The objective of this application is to investigate if pre-B-cell colony enhancing factor (PBEF), AMP-activated protein kinase (AMPK), and phosphodiesterase 1B (PDE1B) play a role in cold-induced pulmonary vascular dysfunction and remodeling for the purpose to develop preventive and therapeutic approaches for PH. The central hypothesis is that intermittent exposure to cold increases pulmonary vascular PBEF which leads to downregulation of AMPK?1 in pulmonary arterial endothelial cells (PA ECs), upregulation of PDE1B in PA SMCs, pulmonary vascular dysfunction and remodeling, and PH, and further, that inhibition of PBEF expression could abolish cold-induced dysregulation of AMPK?1 and PDE1B, PH, and RV hypertrophy. This hypothesis is formulated on strong preliminary data produced in our laboratory. The objective will be achieved by pursuing three interrelated and complemental specific aims using a combination of several novel approaches including in vivo SMC-specific and macrophage-specific gene delivery and real-time monitoring of RV pressure (telemetry). The three specific aims are: (1) Determine if the increase in PBEF plays a role in cold-induced downregulation of AMPK?1 in PA ECs, upregulation of PDE1B in PA SMCs, pulmonary vascular dysfunction and remodeling, and PH. (2) Investigate if the downregulation of endothelial AMPK?1 mediates the role of PBEF in cold-induced pulmonary endothelial dysfunction and PH. (3) Determine if the upregulation of PDE1B and Oct-4 (a transcription factor) mediates the role of PBEF in cold-induced PA SMC proliferation, PA remodeling, and PH. Completion of this work will unveil a novel pathway that mediates CIPH, cold exposure ? PBEF? ? AMPK?1?, PDE1B?, Oct4? ? CIPH. The findings from the proposed research may provide new insights into preventive strategies and therapeutic approaches for PH and related heart diseases. The proposed work is significant for people who live in cold regions and who have outside duties in winter.

Public Health Relevance

People who live and work in cold regions have a high incidence of pulmonary and cardiovascular diseases, indicating that cold temperatures have adverse effects on the human pulmonary and cardiovascular systems. The study of cold-induced pulmonary hypertension is important for people who live in cold regions, for people who have outside duties in winter, for soldiers who fight in a winter battlefield, and also for people who work daily in artificial cold environments, e.g. meat packers, butchers, custodians of freezer lockers, and ice cream manufacturers. The proposed research will benefit the general public because it will lead to the development of preventive strategies and therapeutic approaches for cold-related pulmonary vascular dysfunction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Xiao, Lei
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University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
United States
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Sun, Zhongjie (2015) Aging, arterial stiffness, and hypertension. Hypertension 65:252-6
Sun, Zhongjie (2014) Platelet TLR4: a critical link in pulmonary arterial hypertension. Circ Res 114:1551-3
Crosswhite, Patrick; Chen, Kai; Sun, Zhongjie (2014) AAV delivery of tumor necrosis factor-? short hairpin RNA attenuates cold-induced pulmonary hypertension and pulmonary arterial remodeling. Hypertension 64:1141-50
Crosswhite, Patrick; Sun, Zhongjie (2014) Molecular mechanisms of pulmonary arterial remodeling. Mol Med 20:191-201
Crosswhite, Patrick; Sun, Zhongjie (2013) Inhibition of phosphodiesterase-1 attenuates cold-induced pulmonary hypertension. Hypertension 61:585-92