PhyMedExp, Université de Montpellier, INSERM, CNRS, 34295 Montpellier, France.
PhyMedExp, Université de Montpellier, INSERM, CNRS, CHU de Montpellier, 34295 Montpellier, France.
Int J Mol Sci. 2023 Aug 9;24(16):12609. doi: 10.3390/ijms241612609.
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease involving airway closure and parenchyma destruction (emphysema). Cardiovascular diseases are the main causes of morbi-mortality in COPD and, in particular, hypertension and heart failure with preserved ejection fraction (HFpEF). However, no mechanistic link has currently been established between the onset of COPD, elevated blood pressure (BP) and systemic vascular impairment (endothelial dysfunction). Thus, we aimed to characterize BP and vascular function and remodeling in a rat model of exacerbated emphysema focusing on the role of sympathetic hyperactivity. Emphysema was induced in male Wistar rats by four weekly pulmonary instillations of elastase (4UI) and exacerbation by a single dose of lipopolysaccharides (LPS). Five weeks following the last instillation, in vivo and ex vivo cardiac and vascular functions were investigated. Exacerbated emphysema induced cardiac dysfunction (HFpEF) and a BP increase in this COPD model. We observed vasomotor changes and hypotrophic remodeling of the aorta without endothelial dysfunction. Indeed, changes in contractile and vasorelaxant properties, though endothelium-dependent, were pro-relaxant and NO-independent. A β1-receptor antagonist (bisoprolol) prevented HFpEF and vascular adaptations, while the effect on BP increase was partial. Endothelial dysfunction would not trigger hypertension and HFpEF in COPD. Vascular changes appeared as an adaptation to the increased BP. The preventing effect of bisoprolol revealed a pivotal role of sympathetic hyperactivation in BP elevation. The mechanistic link between HFpEF, cardiac sympathetic activation and BP deserves further studies in this exacerbated-emphysema model, as well as in COPD patients.
慢性阻塞性肺疾病（COPD）是一种涉及气道关闭和实质破坏（肺气肿）的肺部炎症性疾病。心血管疾病是 COPD 患者死亡和发病率的主要原因，尤其是高血压和射血分数保留的心力衰竭（HFpEF）。然而，目前尚未在 COPD 发病、血压升高和全身血管损伤（内皮功能障碍）之间建立起机制联系。因此，我们旨在描述在强调交感神经活性作用的情况下，肺气肿加重模型中大鼠的血压和血管功能及重塑情况。雄性 Wistar 大鼠通过每周四次肺内滴注弹性蛋白酶（4UI）诱导肺气肿，并单次给予脂多糖（LPS）加重肺气肿。最后一次滴注后 5 周，进行体内和离体心脏及血管功能研究。在该 COPD 模型中，加重的肺气肿导致心脏功能障碍（HFpEF）和血压升高。我们观察到血管舒缩变化和主动脉的萎缩性重塑，但没有内皮功能障碍。实际上，尽管收缩和血管舒张特性的改变依赖于内皮，但具有舒张作用且与 NO 无关。β1-受体拮抗剂（比索洛尔）可预防 HFpEF 和血管适应性改变，但对血压升高的作用是部分的。内皮功能障碍不会引发 COPD 中的高血压和 HFpEF。血管变化似乎是对血压升高的一种适应性改变。比索洛尔的预防作用揭示了交感神经过度激活在血压升高中的关键作用。在这种加重性肺气肿模型以及 COPD 患者中，HFpEF、心脏交感神经激活和血压之间的机制联系值得进一步研究。
