Nitric oxide-sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

JCI Insight
Nicola WilckNadine Haase

Abstract

Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide-sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in...Continue Reading

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Citations

Jun 6, 2020·Journal of Cardiovascular Pharmacology·Jin-Lian Shen, Xiao-Jie Xie
May 30, 2020·Journal of the Renin-angiotensin-aldosterone System : JRAAS·Li RongPinfang Kang
Nov 22, 2019·Frontiers in Physiology·Domenico D'AmarioFilippo Crea
May 15, 2019·International Journal of Molecular Sciences·Diana Michels da SilvaTobias Graf
Jul 15, 2020·Journal of Cardiovascular Pharmacology and Therapeutics·Torvind NæsheimTruls Myrmel
Jun 12, 2020·Circulation·Maria ErcuEnno Klussmann

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Datasets Mentioned

BETA
GSE108904

Methods Mentioned

BETA
ELISA
PCR
Chip
chips

Clinical Trials Mentioned

NCT02861534

Software Mentioned

Affymetrix GeneChip Command
Visual Sonics Vevo Strain
Genedata Expressionist Refiner
LOWESS
GeneTitan
Hugo Elektronik
LabChart
7500
KS
Image J

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