Cell therapy attenuates endothelial dysfunction in hypertensive rats with heart failure and preserved ejection fraction

Abstract

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 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.

Renal Denervation Helps Preserve the Ejection Fraction by Pre-Serving Endocardial-Endothelial Function During Heart Failure

“…However, it is unclear whether volume overload activates the renal sympathetic nerve, helps excrete the exosomes containing erythropoietin (EPO), and increase the regeneration capacity of the heart. Recently, Marban and colleagues have shown that cell therapy preserves ejection fraction (EF) via the vascular endothelium [26]. Here we show that renal denervation preserves ejection fraction via endocardial endothelium.…”

A potential role of autophagy-mediated vascular senescence in the pathophysiology of HFpEF

“…CDCs treatment improved EC-dependent vasodilation, reduced oxidative stress, restored endothelial NOS (eNOS) expression, previously shown to be decreased in the HFpEF endothelium ( 31 ), inflammatory response and VCAM-1 expression. It also improved diastolic dysfunction and restored vascular reactivity ( 30 ). These results uncover the importance of microvascular dysfunction in HFpEF.…”

“…Recently, using cell therapy, de Couto et al, ( 30 ) administered intracoronary cardiosphere-derived cells (CDCs) during two weeks to HFpEF rats, developed by feeding Dahl salt-sensitive rats with a high salt diet. CDCs treatment improved EC-dependent vasodilation, reduced oxidative stress, restored endothelial NOS (eNOS) expression, previously shown to be decreased in the HFpEF endothelium ( 31 ), inflammatory response and VCAM-1 expression.…”

Targeting inflammation in hypertension

“…Again, no effects on arterial pressure were observed. Experimental cell therapy with cardiosphere-derived cells (CDCs) improved endothelial function by enhancing nitric oxide production and inhibiting expression of endothelial pro-inflammatory molecules like Vascular cell adhesion protein 1 [39]. CDCs also decreased levels of IL-6 and IL-1b and protected from hypertension induced cardiac damage, without affecting arterial pressure.…”