Abstract
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.
Highlights
Previous studies from our laboratory have demonstrated that cardiac muscle physiology is associated with cell metabolism, cell migration, cell spreading, and cell contraction that are analogous to contraction and relaxation of the cardiac cycle (Tyagi, 1997a,b; Tummalapalli and Tyagi, 1999)
The signal outside-in is instigated by integrins, connexins, matrix metalloproteinase 2 (MMP-2), protease-activated receptor-1 (PAR1), G protein-coupled receptor (GPCR), and as we knew that G protein alpha s subunit (Gαs) is linked to protein kinase B (PKB) (AKT) that causes the cell metabolic synthesis (Azevedo et al, 2001; Cox et al, 2002; Ciccarelli et al, 2021)
The exosomes isolated from remote ischemic conditioning (RIC) groups revealed elevated levels of musclin, Beta 2-AR, CD71, and vascular endothelial growth factor (VEGF)
Summary
Previous studies from our laboratory have demonstrated that cardiac muscle physiology is associated with cell metabolism, cell migration, cell spreading, and cell contraction that are analogous to contraction and relaxation of the cardiac cycle (Tyagi, 1997a,b; Tummalapalli and Tyagi, 1999). Subsequently, Gαs links to focal adhesion kinase (FAK) and causes cell spreading and relaxation This linkage is broken by calpain that results in cell contraction (Figure 1A). The hypothesis of this study is that RIC releases exosomes from skeletal muscle containing inciting molecules such as musclin, the myokine, and that mitigates the CHF (Figure 1B). The premises of this study are that the hindlimb RIC produces full ischemia to the leg and in that process releases exosomes, muscle hormones such as musclin, and that provides systemic, as well as cardiac muscle protection (Subbotina et al, 2015)
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