# Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $732,803

## Abstract

SUMMARY
Sarcolemmal ATP-sensitive K+ (KATP) channels are abundantly expressed in the heart. Several groups have
now identified a key role for these channels in mediating cardioprotection against ischemic injury and their
participation in the protective mechanism of ischemic preconditioning. In the heart there several different
subtypes of KATP channels and little is known about the roles during ischemia and reperfusion. Of particular
interest are the KATP channel subtypes present in the coronary smooth muscle (SM) and coronary endothelial
cells (EC). There is increasing focus on these coronary channels as a target for blood flow regulation and
cardioprotection, yet they are relatively poorly understood. The SM and EC KATP channels are distinct from
ventricular KATP channels and they are also distinct from each other. A major barrier to our understanding of
their respective roles during a complex event such as myocardial ischemia is the lack of currently available
resources specifically to study these two channel subtypes. We have generated novel genetic mouse models
that can distinguish these subtypes of KATP channels and show with one of these that EC KATP channels
strongly participate in myocardial protection during ischemia/reperfusion. The goal of the proposed studies is
systematically to examine the role(s) of the EC and SM KATP channel subtypes in the regulation of coronary
blood flow, protection during ischemia and the protective response to ischemic preconditioning. We
hypothesize that both EC and SM KATP channel subtypes contribute to the regulation of coronary blood
flow and cardioprotection, but through distinctly different mechanisms. Using novel and validated
conditional knockout mice, we will specifically target EC or SM KATP channel subtypes. The proposed studies
have three Aims. In Aim 1, we will investigate the roles of these two coronary KATP channel subtypes in blood
flow during ischemia. We will use isolated, pressurized microvessels and isolated, perfused hearts under
normal, hypoxic and ischemic conditions. We will additionally investigate the role of EC and SM KATP channels
in the myocardial “no-reflow” phenomenon. Aim 2 will investigate the roles of EC and SM KATP channels in
myocardial protection using an in vivo murine I/R model and investigate pathways that regulate infarct
development. Aim 3 will investigate the contribution of EC and SM KATP channel subtypes during ischemic
preconditioning using an in vivo murine I/R model and cellular assays. We will also examine trafficking of these
KATP channel subtypes as a potential protective mechanism and investigate molecular signaling pathways
involved. This multi-investigator proposal combines the expertise of three highly established investigators; Dr.
Lefer’s extensive expertise with in vivo cardiac ischemia/reperfusion models, and Dr. Coetzee’s track record of
studying KATP channels with electrophysiological, biochemical and molecular approaches and Dr. Tinker’s
expertise...

## Key facts

- **NIH application ID:** 10839729
- **Project number:** 7R01HL146514-05
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** William A Coetzee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $732,803
- **Award type:** 7
- **Project period:** 2023-08-17 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839729

## Citation

> US National Institutes of Health, RePORTER application 10839729, Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury (7R01HL146514-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10839729. Licensed CC0.

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