Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Japan.
Physiol Rep. 2023 Nov;11(22):e15788. doi: 10.14814/phy2.15788.
Titin-dependent stiffening of cardiomyocytes is a significant contributor to left ventricular (LV) diastolic dysfunction in heart failure with preserved LV ejection fraction (HFpEF). Small heat shock proteins (HSPs), such as HSPB5 and HSPB1, protect titin and administration of HSPB5 in vitro lowers cardiomyocyte stiffness in pressure-overload hypertrophy. In humans, oral treatment with geranylgeranylacetone (GGA) increases myocardial HSP expression, but the functional implications are unknown. Our objective was to investigate whether oral GGA treatment lowers cardiomyocyte stiffness and attenuates LV diastolic dysfunction in a rat model of the cardiometabolic syndrome. Twenty-one-week-old male lean (n = 10) and obese (n = 20) ZSF1 rats were studied, and obese rats were randomized to receive GGA (200 mg/kg/day) or vehicle by oral gavage for 4 weeks. Echocardiography and cardiac catheterization were performed before sacrifice at 25 weeks of age. Titin-based stiffness (F ) was determined by force measurements in relaxing solution with 100 nM [Ca ] in permeabilized cardiomyocytes at sarcomere lengths (SL) ranging from 1.8 to 2.4 μm. In obese ZSF1 rats, GGA reduced isovolumic relaxation time of the LV without affecting blood pressure, EF or LV weight. In cardiomyocytes, GGA increased myofilament-bound HSPB5 and HSPB1 expression. Vehicle-treated obese rats exhibited higher cardiomyocyte stiffness at all SLs compared to lean rats, while GGA reduced stiffness at SL 2.0 μm. In obese ZSF1 rats, oral GGA treatment improves cardiomyocyte stiffness by increasing myofilament-bound HSPB1 and HSPB5. GGA could represent a potential novel therapy for the early stage of diastolic dysfunction in the cardiometabolic syndrome.
肌联蛋白依赖性心肌细胞僵硬是射血分数保留的心力衰竭（HFpEF）左心室（LV）舒张功能障碍的重要原因。小分子热休克蛋白（HSPs），如 HSPB5 和 HSPB1，可保护肌联蛋白，体外给予 HSPB5 可降低压力超负荷肥厚心肌细胞的僵硬度。在人类中，口服香叶基丙酮（GGA）可增加心肌 HSP 的表达，但功能意义尚不清楚。我们的目的是研究口服 GGA 治疗是否可降低代谢综合征大鼠模型中的心肌细胞僵硬度并减轻 LV 舒张功能障碍。研究了 21 周龄的雄性 lean（n = 10）和肥胖（n = 20）ZSF1 大鼠，肥胖大鼠随机接受 GGA（200 mg/kg/天）或口服灌胃载体 4 周。在 25 周龄时进行安乐死之前进行超声心动图和心导管检查。在松弛溶液中用 100 nM [Ca ]测定肌联蛋白为基础的僵硬度（F ），在松弛溶液中用 100 nM [Ca ]测定在肌节长度（SL）为 1.8 至 2.4 μm的通透心肌细胞中的力。在肥胖的 ZSF1 大鼠中，GGA 降低了 LV 的等容舒张时间，而不影响血压、EF 或 LV 重量。在心肌细胞中，GGA 增加了肌丝结合 HSPB5 和 HSPB1 的表达。与 lean 大鼠相比，给予载体的肥胖大鼠在所有 SL 下均表现出更高的心肌细胞僵硬度，而 GGA 降低了 SL 2.0 μm 时的僵硬度。在肥胖的 ZSF1 大鼠中，口服 GGA 治疗通过增加肌丝结合的 HSPB1 和 HSPB5 来改善心肌细胞僵硬度。GGA 可能成为代谢综合征舒张功能障碍早期阶段的一种潜在新型治疗方法。
