Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Applied Genomics, Computation and Translational Core, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, California.
Am J Physiol Heart Circ Physiol. 2022 Nov 1;323(5):H892-H903. doi: 10.1152/ajpheart.00287.2022. Epub 2022 Sep 9.
Heart failure with preserved ejection fraction (HFpEF) is defined by increased left ventricular (LV) stiffness, impaired vascular compliance, and fibrosis. Although systemic inflammation, driven by comorbidities, has been proposed to play a key role, the precise pathogenesis remains elusive. To test the hypothesis that inflammation drives endothelial dysfunction in HFpEF, we used cardiosphere-derived cells (CDCs), which reduce inflammation and fibrosis, improving function, structure, and survival in HFpEF rats. Dahl salt-sensitive rats fed a high-salt diet developed HFpEF, as manifested by diastolic dysfunction, systemic inflammation, and accelerated mortality. Rats were randomly allocated to receive intracoronary infusion of CDCs or vehicle. Two weeks later, inflammation, oxidative stress, and endothelial function were analyzed. Single-cell RNA sequencing of heart tissue was used to assay transcriptomic changes. CDCs improved endothelial-dependent vasodilation while reducing oxidative stress and restoring endothelial nitric oxide synthase (eNOS) expression. RNA sequencing revealed CDC-induced attenuation of pathways underlying endothelial cell leukocyte binding and innate immunity. Exposure of endothelial cells to CDC-secreted extracellular vesicles in vitro reduced VCAM-1 protein expression and attenuated monocyte adhesion and transmigration. Cell therapy with CDCs corrects diastolic dysfunction, reduces oxidative stress, and restores vascular reactivity. These findings lend credence to the hypothesis that inflammatory changes of the vascular endothelium are important, if not central, to HFpEF pathogenesis. We tested the concept that inflammation of endothelial cells is a major pathogenic factor in HFpEF. CDCs are heart-derived cell products with verified anti-inflammatory therapeutic properties. Infusion of CDCs reduced oxidative stress, restored eNOS abundance, lowered monocyte levels, and rescued the expression of multiple disease-associated genes, thereby restoring vascular reactivity. The salutary effects of CDCs support the hypothesis that inflammation of endothelial cells is a proximate driver of HFpEF.
射血分数保留型心力衰竭（HFpEF）的定义为左心室（LV）僵硬增加、血管顺应性受损和纤维化。尽管由合并症驱动的全身炎症被认为起着关键作用，但确切的发病机制仍难以捉摸。为了测试炎症驱动 HFpEF 中的内皮功能障碍的假说，我们使用了心脏球源性细胞（CDCs），它们可以减少炎症和纤维化，改善 HFpEF 大鼠的功能、结构和存活率。给予高盐饮食的 Dahl 盐敏感大鼠发展为 HFpEF，表现为舒张功能障碍、全身炎症和加速死亡率。大鼠被随机分配接受冠状动脉内输注 CDCs 或载体。两周后，分析炎症、氧化应激和内皮功能。使用心脏组织的单细胞 RNA 测序来检测转录组变化。CDCs 改善了内皮依赖性血管舒张作用，同时减少了氧化应激并恢复了内皮型一氧化氮合酶（eNOS）的表达。RNA 测序显示，CDC 诱导的内皮细胞白细胞结合和固有免疫的途径发生变化。体外暴露于 CDC 分泌的细胞外囊泡可降低 VCAM-1 蛋白表达并减弱单核细胞黏附和迁移。用 CDCs 进行细胞治疗可纠正舒张功能障碍、减少氧化应激并恢复血管反应性。这些发现为血管内皮炎症变化对 HFpEF 发病机制很重要的假说提供了依据。我们检验了内皮细胞炎症是 HFpEF 的主要致病因素的概念。CDCs 是具有已验证的抗炎治疗特性的心脏源性细胞产物。输注 CDCs 可降低氧化应激、恢复 eNOS 丰度、降低单核细胞水平并恢复多个疾病相关基因的表达，从而恢复血管反应性。CDCs 的有益作用支持内皮细胞炎症是 HFpEF 的直接驱动因素的假说。
