# Cav-3 in Diabetic Myocardial Injury Following Ischemia/Reperfusion

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $390,000

## Abstract

Obesity/diabetes adversely impact myocardial ischemia/reperfusion (MI/R) injury by incompletely understood
mechanisms. Visceral adipocyte (ADp) dysfunction contributes to remote organ injury. However, the molecular
link(s) between dysfunctional ADp and increased MI/R injury remain(s) unidentified. Extracellular vesicles,
particularly exosomes (Exo), are systemic messengers mediating inter-organ communication. However, whether
and how diabetes may alter Exo-mediated ADp-heart communication remain unknown. Our preliminary
experiments demonstrate that diabetes causes significant pathologic alterations in both donor (ADp) and
recipient (cardiomyocyte, CM) cells, increasing MI/R injury. This application will test a hypothesis that diabetic
alteration of Exo-mediated ADp to heart communication is a novel mechanism exacerbating post-MI cardiac
remodeling. Three specific aims will be addressed. SA1 will clarify the downstream mechanisms responsible for
diabetic ADp Exo exacerbation of acute MI/R injury. We revealed for the first time that miR-130b-3p is a common
molecule significantly increased in diabetic ADp Exo and diabetic patient serum. MiR-130b-3p mimics
exacerbated MI/R injury, whereas miR130b-3p inhibitor mitigated acute MI/R injury. Experiments in this aim will
1) define ADp as the cellular source of miR-130b-3p in the diabetic heart; and 2) identify the downstream
molecular targets mediating the pro-apoptotic effect of miR-130b-3p. SA2 will identify mechanisms responsible
for increased uptake of ADp Exo by diabetic CM. Preliminary data suggest that reduced Cav3 expression and
increased Cav3 nitration in the diabetic heart is likely responsible for the loss of ADp Exo transmembrane
signaling and promotion of ADp Exo uptake by CM. Combining genetic and pharmacologic approaches, we will
rigorously test a novel hypothesis that Cav3/AdipoR1 signaling complex integrity is critical in determining the fate
of ADp Exo. Diabetic dissociation of cardiac Cav3/AdipoR1 switches AdipoR1 from a receptor mediating ADp-
derived, adiponectin-rich Exo initiated signaling in non-diabetic CM to a vehicle facilitating diabetic ADp Exo
entry within CM. SA3 will test a hypothesis that interventions blocking Exo mediated ADp-CM communication
are novel therapy against diabetic exacerbation of post-MI remodeling and HF. Preliminary data demonstrate
that intramyocardial injection of diabetic ADp Exo exacerbates acute MI/R injury in non-diabetic mice, whereas
Exo production inhibition attenuates MI/R injury in diabetic mice. Experiments in this aim will determine whether
ADp-specific miR-130b-3pKO or CM-specific Cav3OE is effective in protecting the diabetic heart from excessive
post-MI cardiac remodeling. To increase the translational value of our findings, we will determine whether
administration of miR-130b-3p inhibitor or peroxynitrite decomposition catalyst effectively protects against
diabetic ADp Exo-mediated augmented cardiac remodeling and HF. Successful completion...

## Key facts

- **NIH application ID:** 9882390
- **Project number:** 2R01HL123404-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** XIN-LIANG MA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 2
- **Project period:** 2015-09-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882390

## Citation

> US National Institutes of Health, RePORTER application 9882390, Cav-3 in Diabetic Myocardial Injury Following Ischemia/Reperfusion (2R01HL123404-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9882390. Licensed CC0.

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