Remote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure

During acute heart failure (HF), remote ischemic conditioning (RIC) has proven to be beneficial; however, it is currently unclear whether it also extends benefits from chronic congestive, cardiopulmonary heart failure (CHF). Previous studies from our laboratory have shown three phases describing CHF...

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Autores principales:	Rubens P. Homme, Yuting Zheng, Irina Smolenkova, Mahavir Singh, Suresh C. Tyagi
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	congestive heart failure creatine kinase isoforms viral myocarditis matrix metalloproteinases tissue remodeling Physiology QP1-981
Acceso en línea:	https://doaj.org/article/2713615b6ace4a668f5506e3dba71bcc
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spelling	oai:doaj.org-article:2713615b6ace4a668f5506e3dba71bcc2021-11-11T08:44:02ZRemote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure1664-042X10.3389/fphys.2021.745328https://doaj.org/article/2713615b6ace4a668f5506e3dba71bcc2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphys.2021.745328/fullhttps://doaj.org/toc/1664-042XDuring acute heart failure (HF), remote ischemic conditioning (RIC) has proven to be beneficial; however, it is currently unclear whether it also extends benefits from chronic congestive, cardiopulmonary heart failure (CHF). Previous studies from our laboratory have shown three phases describing CHF viz. (1) HF with preserved ejection fraction (HFpEF), (2) HF with reduced EF (HFrEF), and (3) HF with reversed EF. Although reciprocal organ interaction, ablation of sympathetic, and calcium signaling genes are associated with HFpEF to HFrEF, the mechanism is unclear. The HFrEF ensues, in part, due to reduced angiogenesis, coronary reserve, and leakage of endocardial endothelial (EE) and finally breakdown of the blood-heart barrier (BHB) integrity. In fact, our hypothesis states that a change in phenotype from compensatory HFpEF to decompensatory HFrEF is determined by a potential decrease in regenerative, proangiogenic factors along with a concomitant increase in epigenetic memory, inflammation that combinedly causes oxidative, and proteolytic stress response. To test this hypothesis, we created CHF by aorta-vena-cava (AV) fistula in a group of mice that were subsequently treated with that of hind-limb RIC. HFpEF vs. HFrEF transition was determined by serial/longitudinal echo measurements. Results revealed an increase in skeletal muscle musclin contents, bone-marrow (CD71), and sympathetic activation (β2-AR) by RIC. We also observed a decrease in vascular density and attenuation of EE-BHB function due to a corresponding increase in the activity of MMP-2, vascular endothelial growth factor (VEGF), caspase, and calpain. This decrease was successfully mitigated by RIC-released skeletal muscle exosomes that contain musclin, the myokine along with bone marrow, and sympathetic activation. In short, based on proteome (omics) analysis, ∼20 proteins that appear to be involved in signaling pathways responsible for the synthesis, contraction, and relaxation of cardiac muscle were found to be the dominant features. Thus, our results support that the CHF phenotype causes dysfunction of cardiac metabolism, its contraction, and relaxation. Interestingly, RIC was able to mitigate many of the deleterious changes, as revealed by our multi-omics findings.Rubens P. HommeYuting ZhengIrina SmolenkovaMahavir SinghSuresh C. TyagiFrontiers Media S.A.articlecongestive heart failurecreatine kinase isoformsviral myocarditismatrix metalloproteinasestissue remodelingPhysiologyQP1-981ENFrontiers in Physiology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	congestive heart failure creatine kinase isoforms viral myocarditis matrix metalloproteinases tissue remodeling Physiology QP1-981
spellingShingle	congestive heart failure creatine kinase isoforms viral myocarditis matrix metalloproteinases tissue remodeling Physiology QP1-981 Rubens P. Homme Yuting Zheng Irina Smolenkova Mahavir Singh Suresh C. Tyagi Remote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure
description	During acute heart failure (HF), remote ischemic conditioning (RIC) has proven to be beneficial; however, it is currently unclear whether it also extends benefits from chronic congestive, cardiopulmonary heart failure (CHF). Previous studies from our laboratory have shown three phases describing CHF viz. (1) HF with preserved ejection fraction (HFpEF), (2) HF with reduced EF (HFrEF), and (3) HF with reversed EF. Although reciprocal organ interaction, ablation of sympathetic, and calcium signaling genes are associated with HFpEF to HFrEF, the mechanism is unclear. The HFrEF ensues, in part, due to reduced angiogenesis, coronary reserve, and leakage of endocardial endothelial (EE) and finally breakdown of the blood-heart barrier (BHB) integrity. In fact, our hypothesis states that a change in phenotype from compensatory HFpEF to decompensatory HFrEF is determined by a potential decrease in regenerative, proangiogenic factors along with a concomitant increase in epigenetic memory, inflammation that combinedly causes oxidative, and proteolytic stress response. To test this hypothesis, we created CHF by aorta-vena-cava (AV) fistula in a group of mice that were subsequently treated with that of hind-limb RIC. HFpEF vs. HFrEF transition was determined by serial/longitudinal echo measurements. Results revealed an increase in skeletal muscle musclin contents, bone-marrow (CD71), and sympathetic activation (β2-AR) by RIC. We also observed a decrease in vascular density and attenuation of EE-BHB function due to a corresponding increase in the activity of MMP-2, vascular endothelial growth factor (VEGF), caspase, and calpain. This decrease was successfully mitigated by RIC-released skeletal muscle exosomes that contain musclin, the myokine along with bone marrow, and sympathetic activation. In short, based on proteome (omics) analysis, ∼20 proteins that appear to be involved in signaling pathways responsible for the synthesis, contraction, and relaxation of cardiac muscle were found to be the dominant features. Thus, our results support that the CHF phenotype causes dysfunction of cardiac metabolism, its contraction, and relaxation. Interestingly, RIC was able to mitigate many of the deleterious changes, as revealed by our multi-omics findings.
format	article
author	Rubens P. Homme Yuting Zheng Irina Smolenkova Mahavir Singh Suresh C. Tyagi
author_facet	Rubens P. Homme Yuting Zheng Irina Smolenkova Mahavir Singh Suresh C. Tyagi
author_sort	Rubens P. Homme
title	Remote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure
title_short	Remote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure
title_full	Remote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure
title_fullStr	Remote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure
title_full_unstemmed	Remote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure
title_sort	remote hind-limb ischemia mechanism of preserved ejection fraction during heart failure
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/2713615b6ace4a668f5506e3dba71bcc
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Remote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure

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