Investigation into Cold-induced Pulmonary Vascular Inflammation and Dysfunction

描述（由申请人提供）：大量流行病学研究表明，生活在寒冷地区的人有更高的肺部和心血管疾病发病率（见背景）。在美国，肺部和心血管疾病的死亡率和发病率最高的季节是寒冷的冬季。低温会增加肺部和心血管疾病的严重程度。我们的长期目标是了解低温作为心血管功能障碍的危险因素，以制定预防和治疗策略。间歇性中低温（5℃）可引起大鼠肺血管炎症和功能障碍、肺动脉高压和右心室肥厚，即冷致肺动脉高压（CIPH）。动物CIPH（肺动脉高压、肺动脉肥大、丛状病变）的特征与人类特发性PH相似，使其成为研究PH的相关且独特的模型。本应用程序的目的是研究前b细胞集群增强因子（PBEF）， amp活化蛋白激酶（AMPK），和磷酸二酯酶1B （PDE1B）在寒冷诱导的肺血管功能障碍和重塑中发挥作用，目的是为了开发PH的预防和治疗方法。中心假设是间歇性暴露于寒冷会增加肺血管PBEF，从而导致肺动脉内皮细胞（PA ECs）中AMPK¿1的下调，PA SMCs中PDE1B的上调，肺血管功能障碍和重塑，以及PH。抑制PBEF的表达可以消除寒冷诱导的AMPK¿1和PDE1B的失调、PH和RV的肥大。这一假设是根据我们实验室产生的强有力的初步数据制定的。该目标将通过使用几种新方法的组合来实现三个相互关联和互补的特定目标，包括体内smc特异性和巨噬细胞特异性基因传递以及实时监测RV压力（遥测）。三个具体目标是：(1)确定PBEF的升高是否在低温诱导的PA ECs中AMPK¿1的下调、PA SMCs中PDE1B的上调、肺血管功能障碍和重塑以及ph中起作用。(2)研究内皮细胞AMPK¿1的下调是否介导PBEF在低温诱导的肺内皮功能障碍和ph中的作用。(3)确定PDE1B和Oct-4（一种转录因子）的上调是否介导PBEF在低温诱导的PA SMC增殖、PA重塑中的作用。这项工作的完成将揭示介导CIPH、冷暴露¿PBEF¿AMPK¿1¿、PDE1B¿、Oct4¿CIPH的新途径。该研究结果可能为PH及相关心脏病的预防策略和治疗方法提供新的见解。这项工作对那些生活在寒冷地区和冬天有户外工作的人来说意义重大。

DESCRIPTION (provided by applicant): 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.