Heart failure with preserved ejection fraction (HFpEF) is a major health problem without effective therapies. This study assessed the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian model of pressure overload recapitulating features of diastolic dysfunction common to human HFpEF. Male domestic short-hair felines (n = 31, aged 2 months) underwent a sham procedure (n = 10) or loose aortic banding (n = 21), resulting in slow-progressive pressure overload. Two months after banding, animals were treated daily with suberoylanilide hydroxamic acid (b + SAHA, 10 mg/kg, n = 8), a Food and Drug Administration-approved pan-HDAC inhibitor, or vehicle (b + veh, n = 8) for 2 months. Echocardiography at 4 months after banding revealed that b + SAHA animals had significantly reduced left ventricular hypertrophy (LVH) (P < 0.0001) and left atrium size (P < 0.0001) versus b + veh animals. Left ventricular (LV) end-diastolic pressure and mean pulmonary arterial pressure were significantly reduced in b + SAHA (P < 0.01) versus b + veh. SAHA increased myofibril relaxation ex vivo, which correlated with in vivo improvements of LV relaxation. Furthermore, SAHA treatment preserved lung structure, compliance, blood oxygenation, and reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar capillary stress failure. Acetylation proteomics revealed that SAHA altered lysine acetylation of mitochondrial metabolic enzymes. These results suggest that acetylation defects in hypertrophic stress can be reversed by HDAC inhibitors, with implications for improving cardiac structure and function in patients.

中文翻译：

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HDAC 抑制可改善舒张功能障碍猫模型的心肺功能。


射血分数保留的心力衰竭（HFpEF）是一个没有有效治疗方法的主要健康问题。本研究评估了组蛋白脱乙酰酶 (HDAC) 抑制对大型哺乳动物压力超负荷模型中心肺结构、功能和代谢的影响，该模型概括了人类 HFpEF 常见的舒张功能障碍的特征。雄性家养短毛猫（n = 31，2 个月大）接受了假手术（n = 10）或松散主动脉带（n = 21），导致缓慢进行性压力超负荷。条带后两个月，动物每天接受辛二酰苯胺异羟肟酸（b + SAHA，10 mg/kg，n = 8）、美国食品和药物管理局批准的泛 HDAC 抑制剂或载体（b + veh，n = 8）治疗）2个月。结扎后 4 个月的超声心动图显示，与 b + veh 动物相比，b + SAHA 动物的左心室肥厚 (LVH) (P < 0.0001) 和左心房大小 (P < 0.0001) 显着减少。与 b + veh 相比，b + SAHA 的左心室 (LV) 舒张末期压力和平均肺动脉压显着降低 (P < 0.01)。 SAHA 增加离体肌原纤维松弛，这与体内左室松弛的改善相关。此外，SAHA 治疗保留了肺结构、顺应性、血液氧合，并减少了肺泡外血管周围的血管周围液体袖带，表明肺泡毛细血管应力衰竭减轻。乙酰化蛋白质组学表明，SAHA 改变了线粒体代谢酶的赖氨酸乙酰化。这些结果表明，HDAC 抑制剂可以逆转肥厚应激中的乙酰化缺陷，这对于改善患者的心脏结构和功能具有重要意义。