Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.
Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.
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DOI：
10.1161/circulationaha.121.053889
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发表时间：
2021-08-24
期刊：
影响因子：
37.8
通讯作者：
Gladwin MT
中科院分区：
文献类型：
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作者：
Satoh T;Wang L;Espinosa-Diez C;Wang B;Hahn SA;Noda K;Rochon ER;Dent MR;Levine AR;Baust JJ;Wyman S;Wu YL;Triantafyllou GA;Tang Y;Reynolds M;Shiva S;Hilaire CS;Gomez D;Goncharov DA;Goncharova EA;Chan SY;Straub AC;Lai YC;McTiernan CF;Gladwin MT
许多射血分数(HFpEF)保留的心力衰竭患者存在代谢综合征，并发展为运动性肺动脉高压(EIPH)。HFpEF患者肺血管阻力增加预示着预后不良；这种表型称为毛细血管前和毛细血管后肺高压(CPCPH)。EIPH和CPCPH的治疗试验一直令人失望，这表明需要针对上游疾病机制的战略。本工作报道了新的大鼠EIPH模型和肺血管功能障碍的机制，其核心是肺动脉平滑肌细胞(PAVSMCs)中可溶性鸟苷环化酶(SGC)的转录抑制。我们使用肥胖的ZSF-1瘦素受体基因敲除大鼠(HFpEF模型)，用SU5416治疗的肥胖ZSF-1大鼠刺激静息PH(肥胖+SUGEN，CpcPH模型)，以及瘦ZSF-1大鼠(对照组)。在跑台运动中，通过植入导管评价右、左室血流动力学。用MRI和肌造影评价动脉血氧饱和度。通过PA转染腺相关病毒6(AAV6)实现sGCβ1转录增强子NFYA的过表达。治疗组在饮用水中加入SGLT2抑制剂恩帕格列夫秦。用棕榈酸、葡萄糖和胰岛素(PGI)培养大鼠和人的PAVSMCs，诱导代谢应激。肥胖大鼠表现出正常的静息右室收缩压(RVSP)，运动时右室收缩压显著升高，造模为EIPH。肥胖+SUGEN大鼠在安静状态下表现出解剖上的PA重构和RVSP升高，而运动加剧了这一现象。多巴酚丁胺激发时的肌图和MRI显示两个肥胖组的PA功能受损。肥胖大鼠PAS产生活性氧(ROS)，降低sGCβ1的表达。从机制上讲，肥胖大鼠、糖尿病患者和经前列腺素I治疗的大鼠肺血管平滑肌细胞显示线粒体ROS增加，这增加了依赖miR-193B的NFYA的核糖核酸降解，导致sGCβ1-cGMP信号减弱。通过AAV6强制表达NYFA可增加肥胖+肥胖大鼠sGCβ1水平，并改善运动PH值。恩帕格列齐治疗肥胖+SUGEN大鼠可改善代谢综合征，降低线粒体ROS和miR-193B水平，恢复NFYA/sGC活性，并预防EIPH。在HFpEF和CPCPH模型中，代谢综合征通过增加ROS和miR-193B的表达，下调依赖于NFYA的sGCβ1的表达，从而导致肺血管功能障碍和EIPH。AAv介导的NFYA过表达和抑制SGLT2可恢复NFYA-sGCβ1-cGMP信号转导，改善EIPH。
Many patients with heart failure with preserved ejection fraction (HFpEF) have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with HFpEF portend a poor prognosis; this phenotype is referred to as combined pre-and post-capillary PH (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery smooth muscle cells (PAVSMCs). We used obese ZSF-1 leptin-receptor knock-out rats (HFpEF model), obese ZSF-1 rats treated with SU5416 to stimulate resting PH (Obese+sugen, CpcPH model), and Lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated via implanted-catheters during treadmill exercise. PA function was evaluated using MRI and myography. Overexpression of NFYA, a transcriptional-enhancer of sGCβ1, was performed by PA delivery of adeno-associated-virus 6 (AAV6). Treatment groups received SGLT2 inhibitor Empagliflozin in drinking water. PAVSMCs from rats and humans were cultured with Palmitic acid, Glucose, and Insulin (PGI) to induce metabolic-stress. Obese rats showed normal resting right ventricular systolic pressures (RVSP) which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomical PA remodeling and developed elevated RVSP at rest, which was exacerbated with exercise, modeling CpcPH. Myography and MRI during dobutamine-challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species (ROS) and decreased sGCβ1 expression. Mechanistically, cultured PAVSMCs from obese rats, humans with diabetes or treated with PGI, showed increased mitochondrial-ROS, which enhanced miR-193b-dependent RNA-degradation of NFYA, resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by AAV6 delivery increased sGCβ1 levels and improved exercise-PH in Obese+sugen rats. Treatment of Obese+sugen rats with Empagliflozin improved metabolic syndrome, reduced mitochondrial ROS and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. In HFpEF and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced ROS and miR-193b expression, which down-regulates NFYA-dependent sGCβ1 expression. AAV-mediated NFYA overexpression and SGLT2 inhibition restores NFYA-sGCβ1-cGMP signaling and ameliorates EIPH.