Homme Rubens P, Zheng Yuting, Smolenkova Irina, Singh Mahavir, Tyagi Suresh C
Department of Physiology, University of Louisville School of Medicine, Louisville, KY, United States.
Front Physiol. 2021 Nov 11;12:745328. doi: 10.3389/fphys.2021.745328. eCollection 2021.
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.
在急性心力衰竭（HF）期间，远程缺血预处理（RIC）已被证明是有益的；然而，目前尚不清楚它是否也能为慢性充血性心肺心力衰竭（CHF）带来益处。我们实验室之前的研究已经表明CHF有三个阶段，即：（1）射血分数保留的心力衰竭（HFpEF），（2）射血分数降低的心力衰竭（HFrEF），以及（3）射血分数逆转的心力衰竭。尽管相互的器官相互作用、交感神经消融以及钙信号基因与HFpEF向HFrEF的转变有关，但其机制尚不清楚。HFrEF部分是由于血管生成减少、冠状动脉储备降低、心内膜内皮（EE）渗漏，最终导致血心屏障（BHB）完整性破坏而发生的。事实上，我们的假设表明，从代偿性HFpEF到失代偿性HFrEF的表型变化是由再生、促血管生成因子的潜在减少以及表观遗传记忆、炎症的同时增加共同导致的，这些因素共同引起氧化应激和蛋白水解应激反应。为了验证这一假设，我们通过主动脉 - 腔静脉（AV）瘘在一组小鼠中制造了CHF，随后对其进行后肢RIC治疗。通过连续/纵向超声心动图测量来确定HFpEF与HFrEF的转变。结果显示，RIC使骨骼肌中肌肉素含量、骨髓（CD71）以及交感神经激活（β2 - AR）增加。我们还观察到，由于基质金属蛋白酶 - 2（MMP - 2）、血管内皮生长因子（VEGF）、半胱天冬酶和钙蛋白酶活性相应增加，血管密度降低，EE - BHB功能减弱。含有肌肉素、骨髓和交感神经激活的RIC释放的骨骼肌外泌体成功减轻了这种降低。简而言之，基于蛋白质组（组学）分析，发现约20种似乎参与负责心肌合成、收缩和舒张信号通路的蛋白质是主要特征。因此，我们的结果支持CHF表型导致心脏代谢、收缩和舒张功能障碍。有趣的是，正如我们的多组学研究结果所示，RIC能够减轻许多有害变化。
