Khoury Emad E, Kinaneh Safa, Aronson Doron, Amir Offer, Ghanim Diab, Volinsky Natalia, Azzam Zaher, Abassi Zaid
Department of Physiology, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Department of Cardiology, Rambam Health Care Campus, Haifa, Israel.
Oncotarget. 2018 Apr 24;9(31):21715-21730. doi: 10.18632/oncotarget.24922.
Congestive heart failure (CHF) often leads to progressive cardiac hypertrophy and salt/water retention as evident by peripheral and lung edema. Although the pathogenesis of CHF remains largely unclarified, it is widely accepted that neurohormonal changes and inflammatory processes are profoundly involved in structural and functional deterioration of vital organs including, heart, kidney and lungs. Corin, a cardiac serine protease, is responsible for converting pro-ANP and pro-BNP to biologically active natriuretic peptides (NPs). Although the involvement of corin in cardiac hypertrophy and heart failure was extensively studied, the alterations in corin and PCSK6, a key enzyme in the conversion of procorin to corin, have not been studied in the pulmonary tissue. Thus, this study aims at examining the status of PCSK6/Corin in the lung of rats with CHF induced by the creation of aorto-caval fistula (ACF) between the abdominal aorta and vena cava in SD rats. Rats with ACF were divided into 2 subgroups based on the pattern of their daily sodium excretion, compensated and decompensated CHF. Placement of ACF led to cardiac hypertrophy, pulmonary congestion, and renal dysfunction, which were more severe in the decompensated subgroup, despite remarkable elevation of circulatory ANP and BNP levels. Corin mRNA and immunoreactive peptide were detected in pulmonary tissue of all experimental groups. However, the expression and abundance of pulmonary corin significantly increased in the decompensated animals, but not in the compensated ones. Noteworthy, the expression of PCSK6 and ANP/BNP in the pulmonary tissue followed a similar pattern as corin. The upregulation of pulmonary Corin/PCSK6 and NPs were accompanied by local activation of cathepsin L and certain cytokines including IL-6. In light of the anti-inflammatory role of NPs, we postulate that the obtained upregulation of pulmonary PCSK6/Corin along NPs in rats with decompensated CHF may represent a counterbalance response to the inflammatory milieu characterizing CHF especially in severe cases.
充血性心力衰竭（CHF）常导致进行性心脏肥大和盐/水潴留，外周和肺水肿即为明证。尽管CHF的发病机制在很大程度上仍未阐明，但人们普遍认为神经激素变化和炎症过程与包括心脏、肾脏和肺在内的重要器官的结构和功能恶化密切相关。Corin是一种心脏丝氨酸蛋白酶，负责将前心钠素（pro-ANP）和前脑钠肽（pro-BNP）转化为具有生物活性的利钠肽（NPs）。尽管对Corin在心脏肥大和心力衰竭中的作用进行了广泛研究，但尚未对肺组织中Corin和PCSK6（将前Corin转化为Corin的关键酶）的变化进行研究。因此，本研究旨在检测通过在SD大鼠腹主动脉和腔静脉之间建立主动脉-腔静脉瘘（ACF）诱导的CHF大鼠肺组织中PCSK6/Corin的状态。根据每日钠排泄模式，将ACF大鼠分为两个亚组，即代偿性和失代偿性CHF。尽管循环中的ANP和BNP水平显著升高，但ACF的建立导致了心脏肥大、肺充血和肾功能障碍，在失代偿亚组中更为严重。在所有实验组的肺组织中均检测到Corin mRNA和免疫反应性肽。然而，失代偿动物肺组织中Corin的表达和丰度显著增加，而代偿动物则没有。值得注意的是，肺组织中PCSK6和ANP/BNP的表达与Corin的模式相似。肺组织中Corin/PCSK6和NPs的上调伴随着组织蛋白酶L和某些细胞因子（包括IL-6）的局部激活。鉴于NPs的抗炎作用，我们推测在失代偿性CHF大鼠中肺组织PCSK6/Corin与NPs的上调可能代表了对CHF特征性炎症环境的一种平衡反应，尤其是在严重病例中。
