Investigation into Cold-induced Pulmonary Vascular Inflammation and Dysfunction

描述（申请人提供）：大量流行病学研究表明，生活在寒冷地区的人肺部和心血管疾病的发病率较高（见背景）。在美国，肺部和心血管疾病导致的死亡率和发病率最高发生在寒冷的冬季。寒冷的气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是心血管功能障碍的危险因素，以制定预防和治疗策略。间歇性暴露于中度寒冷（5℃）下会导致大鼠肺血管炎症和功能障碍、肺动脉高压和右心室（RV）肥厚，即冷诱发肺动脉高压（CIPH）。动物 CIPH（高肺动脉压、肺动脉肥大、丛状病变）的特征与人类特发性 PH 的特征相似，使其成为研究 PH 的相关且独特的模型。本申请的目的是研究前 B 细胞集落增强因子 (PBEF)、AMP 激活蛋白激酶 (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是否发挥作用，以开发 PH 的预防和治疗方法。核心假设是，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 EC) 中 AMPK¿1 下调、PA SMC 中 PDE1B 上调、肺血管功能障碍和重塑以及 PH，此外，抑制 PBEF 表达可以消除寒冷诱导的 AMPK¿1 和 PDE1B 失调、PH 和 RV 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。该目标将通过结合多种新方法来实现三个相互关联和互补的具体目标，包括体内 SMC 特异性和巨噬细胞特异性基因传递以及 RV 压力实时监测（遥测）。三个具体目标是：（1）确定 PBEF 的增加是否在寒冷诱导的 PA EC 中 AMPK¿1 下调、PA SMC 中 PDE1B 上调、肺血管功能障碍和重塑以及 PH 中发挥作用。 (2) 探讨内皮AMPK¿1的下调是否介导PBEF在寒冷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 在冷诱导的 PA SMC 增殖、PA 重塑和 PH 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。拟议研究的结果可能为 PH 和相关心脏病的预防策略和治疗方法提供新的见解。这项工作对于生活在寒冷地区和冬季外出工作的人们来说具有重要意义。

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.