Interleukin-1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis.
Interleukin-1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis.
复制标题
DOI：
10.1161/jaha.122.029668
复制
发表时间：
2023-07-18
影响因子：
5.4
通讯作者：
Matrougui, Khalid
中科院分区：
文献类型：
--
作者：
Srinivas, Balaji K.;Bourdi, Aya;O'Regan, Jacob D.;Malavalli, Kumar D.;Rhaleb, Nour-Eddine;Belmadani, Souad;Matrougui, Khalid
心力衰竭伴保留射血分数(HFpEF)是心血管医学中一个重要的未得到满足的需求，并且仍然是一种无法治疗的心血管疾病。白介素1β在高血压性肺间质纤维化发病机制中的作用和机制尚不清楚。将C57/Bl6J和白细胞介素1β−/−雄性小鼠随机分为4组。第1组和第2组：C57/Bl6J和IL-1β−/−小鼠按常规饲料饲养4个 月，作为对照组。第3组和第4组：C57/BL6和IL-1β−/−小鼠在饮水中加入N[w]-硝基-L-精氨酸甲酯(内皮型一氧化氮合酶抑制剂，0.5 g/L)，高脂饲料喂养4个 月。我们测量了体重、血压、糖尿病状态、心功能/肥大/炎症、纤维化、血管内皮功能和信号。C57/BL6小鼠给予高脂饮食和饮水中N[w]-硝基-L-精氨酸甲酯4个 月后，出现以肥胖、糖尿病、高血压、心肌肥大、肺水肿、运动能力低下、大血管和微血管内皮功能障碍、舒张性心功能障碍为特征的病理改变，但心脏射血分数与对照组相比无明显变化。有趣的是，白介素1β的基因破坏通过调节炎症和内质网应激机制来保护小鼠免受高血压性肺泡灌洗的影响。我们的数据表明，白介素1β可能通过调节炎症和内质网应激途径，在高血压性肺间质纤维化的发病过程中起关键作用。我们的发现为HFpEF治疗提供了一个潜在的治疗靶点。
Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin‐1β in HFpEF pathogenesis are poorly understood. C57/Bl6J and interleukin‐1β−/− male mice were randomly divided into 4 groups. Groups 1 and 2: C57/Bl6J and interleukin‐1β−/− mice were fed a regular diet for 4 months and considered controls. Groups 3 and 4: C57/Bl6 and interleukin‐1β−/− mice were fed a high‐fat diet with N[w]‐nitro‐l‐arginine methyl ester (endothelial nitric oxide synthase inhibitor, 0.5 g/L) in the drinking water for 4 months. We measured body weight, blood pressure, diabetes status, cardiac function/hypertrophy/inflammation, fibrosis, vascular endothelial function, and signaling. C57/Bl6 fed a high‐fat diet and N[w]‐nitro‐l‐arginine methyl ester in the drinking water for 4 months developed HFpEF pathogenesis characterized by obesity, diabetes, hypertension, cardiac hypertrophy, lung edema, low running performance, macrovascular and microvascular endothelial dysfunction, and diastolic cardiac dysfunction but no change in cardiac ejection fraction compared with control mice. Interestingly, the genetic disruption of interleukin‐1β protected mice from HFpEF pathogenesis through the modulation of the inflammation and endoplasmic reticulum stress mechanisms. Our data suggest that interleukin‐1β is a critical driver in the development of HFpEF pathogenesis, likely through regulating inflammation and endoplasmic reticulum stress pathways. Our findings provide a potential therapeutic target for HFpEF treatment.