Natriuretic peptide receptor C contributes to disproportionate right ventricular hypertrophy in a rodent model of obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension
Natriuretic peptide receptor C contributes to disproportionate right ventricular hypertrophy in a rodent model of obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension
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DOI：
10.1177/2045894019895452
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发表时间：
2019-10-01
影响因子：
2.6
通讯作者：
Hemnes, Anna R.
中科院分区：
文献类型：
--
作者：
Agrawal, Vineet;Fortune, Niki;Hemnes, Anna R.
射血分数保留的心力衰竭（HFpEF）目前尚无可提高死亡率的治疗方法。右心室功能障碍和肺动脉高压在 HFpEF 中很常见，并且被认为是由肥胖和代谢综合征引起的。因此，我们假设肥胖引起的 HFpEF 合并肺动脉高压的动物模型将有助于深入了解 HFpEF 右心室衰竭的发病机制。两种小鼠品系，一种对肥胖引起的 HFpEF 敏感 (AKR) 和一种抗性 (C3H)，分别喂食高脂肪（60% 脂肪）或对照饮食 0、2 或 20 周，并通过心导管检查和超声心动图评估右心室功能障碍、肺动脉高压和 HFpEF 的发生情况。 AKR（而非 C3H）小鼠出现右心室功能障碍、肺动脉高压和 HFpEF。 NPRC 可以拮抗有益的利尿钠肽信号传导，在发生肺动脉高压和 HFpEF 的 AKR 小鼠的 RNA 测序中发现，NPRC 是右心室中差异最大的基因，但左心室或肺中则不然。 H9C2 细胞中 NPRC 的过度表达增加了基底细胞的大小并增加了肥大基因 MYH7 和 NPPA 的表达。总之，我们发现 NPRC 通过增加心肌细胞肥大，有助于肥胖诱导的肺动脉高压 - HFpEF 的右心室模型。 NPRC 可能是肺动脉高压（HFpEF）右心室功能障碍的一个有前景的治疗靶点。
Heart failure with preserved ejection fraction (HFpEF) currently has no therapies that improve mortality. Right ventricular dysfunction and pulmonary hypertension are common in HFpEF, and thought to be driven by obesity and metabolic syndrome. Thus, we hypothesized that an animal model of obesity-induced HFpEF with pulmonary hypertension would provide insight into the pathogenesis of right ventricular failure in HFpEF. Two strains of mice, one susceptible (AKR) and one resistant (C3H) to obesity-induced HFpEF, were fed high fat (60% fat) or control diet for 0, 2, or 20 weeks and evaluated by cardiac catheterization and echocardiography for development of right ventricular dysfunction, pulmonary hypertension, and HFpEF. AKR, but not C3H, mice developed right ventricular dysfunction, pulmonary hypertension, and HFpEF. NPRC, which antagonizes beneficial natriuretic peptide signaling, was found in RNA sequencing to be the most differentially upregulated gene in the right ventricle, but not left ventricle or lung, of AKR mice that developed pulmonary hypertension and HFpEF. Overexpression of NPRC in H9C2 cells increased basal cell size and increased expression of hypertrophic genes, MYH7 and NPPA. In conclusion, we have shown that NPRC contributes to right ventricular modeling in obesity-induced pulmonary hypertension-HFpEF by increasing cardiomyocyte hypertrophy. NPRC may represent a promising therapeutic target for right ventricular dysfunction in pulmonary hypertension-HFpEF.