# Remote Hind Limb Ischemia Mechanism of Cardioprotection

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2021 · $64,876

## Abstract

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 β synthase
(CBS) and cystathionine γ 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.

## Key facts

- **NIH application ID:** 10247852
- **Project number:** 3R01HL139047-03S1
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Suresh C. Tyagi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $64,876
- **Award type:** 3
- **Project period:** 2020-12-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247852

## Citation

> US National Institutes of Health, RePORTER application 10247852, Remote Hind Limb Ischemia Mechanism of Cardioprotection (3R01HL139047-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10247852. Licensed CC0.

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