Although hind limb remote ischemic conditioning (RIC) is cardioprotective, the mechanism is unknown. The long-term goal of this project is to understand the mechanism of protection by remote hind-limb ischemia. The central hypothesis of this proposal is that transient ischemic episodes, away from the myocardial infarction (MI), contribute to the recovery through secretion of beneficial exosomes from skeletal muscle endocrine, improving mitochondrial metabolism, hydrogen sulfide (H2S, an anti-oxidant, anti-inflammatory, anti-apoptotic, vasoactive gas) and mobilization of bone marrow stem cells (BMSC) to the site of injury (Figure 1). It is known that DNA hypermethylation by epigenetic modification inhibits the gene and produces homocysteine (Hcy), leading to hyperhomocysteinemia (HHcy) that decreases H2S. Interestingly, increase in cystathione ? synthase (CBS) and cystathionine ? lyase (CSE) enzymes increases H2S and decreases Hcy. Our preliminary data suggests that RIC induced musclin (a skeletal muscle hormone) attenuated myocardial muscle damage and dysfunction. The central hypothesis will be tested by the following three specific aims:
Specific Aim 1 : To determine whether the RIC releases exosomes, induces musclin and reverses compromised skeletal and cardiac muscle function during MI and diabetes.
Specific Aim 2 : To determine whether the RIC enhances H2S production by increasing CBS and CSE expression, and epigenetic hypomethylation and gene induction during MI and diabetes.
Specific Aim 3 : To determine whether the RIC instigates BMSC mobilization to the site of myocardial injury and mitigates muscle damage by regeneration after MI during diabetes.
The incidence of coronary heart disease (CHD) in diabetics is robust and this proposal addresses the issue of remote ischemia can create beneficial effects on ischemic insult in the heart. There must be a strategy to restore lost ischemic tolerance capacity in diabetes to counter the risk. Our proposal focuses on this aspect and evaluates mechanisms of remote ischemic condition (RIC) in effective treatment of myocardial infarction (MI).
