# SKca/IKca Channel Activation and Endothelial Protection During Cardiac Surgery

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2020 · $391,491

## Abstract

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, which predisposes to ischemic
cardiovascular events. These vascular disturbances may increase morbidity and mortality in diabetic patients. Endothelial
dysfunction from diabetes is associated with altered metabolism and inactivation of small (SKCa) and intermediate (IKCa)
conductance calcium-activated-potassium channels in the animal and human coronary vasculature. However, the precise
mechanisms responsible for diabetic inactivation of SKCa/IKCa and coronary endothelial dysfunction are still undefined.
Recently, we demonstrated that elevation in intracellular NADH results in a significant decrease in endothelial SKCa/IKCa,
and the lack of changes in SKCa/IKCa gene/protein abundances in the setting of diabetes and ischemia/reperfusion (I/R)
suggests that the effect is post-translational. The goal of this project is to investigate how metabolic changes during
diabetes negatively regulate SKCa/IKCa channels of animal/human endothelial cells and endothelial function in the
animal/human coronary microvasculature and to evaluate if SKCa/IKCa activation and/or metabolic modulation protect
endothelial cells/vessels against diabetes and ischemic insults. We hypothesize that persistent overproduction of reactive
oxygen species (ROS) via NADPH oxidase (Nox), dysfunctional mitochondria and PKC during diabetes will result in 1)
inactivation of endothelial SKCa/IKCa, 2) impairment of coronary endothelial function/arteriolar relaxation; and that 3)
inhibition of Nox and mROS and/or PKC SKCa/IKCa overexpression may potentiate SKCa/IKCa activator-induced endothelial
protection of endothelial cells/coronary arterioles against a simulated cardioplegia I/R injury. Using a type-2 diabetic mice
model and heart/vessels/endothelial cell samples from patients, we will test our hypothesis by completing 4 specific aims.
Aim 1 will investigate the molecular mechanisms by which persistent over-expression/activation of NADH/Nox during
diabetes results in mROS and PKC overproduction/activation, leading to SKCa/IKCa inactivation, endothelial
dysfunction/impaired vasodilatation, Aim 2 will elucidate the mechanisms by which persistent increases in mROS from
the mitochondrial complex are required for diabetic inactivation of SKCa/IKCa, and endothelial function and arteriolar
vasodilatation. Aim 3 will define the signaling pathways by which persistent PKC activation during diabetes negatively
modifies SKCa/IKCa, and coronary endothelial function and microvascular relaxation. These experiments will also determine
if PKC mediates its effects on the SKCa/IKCa channel either by direct action on the channel complex or by causing channel
isolation from the sarcolemma. Aim 4: To examine if pharmacologic inhibition/gene knockdown of Nox, mROS, PKC and/or
SKCa/IKCa overexpression may potentiate SKCa/IKCa activator-induced endothelial protection against a simulated
cardioplegic I/R injury. To achieve ...

## Key facts

- **NIH application ID:** 9919369
- **Project number:** 5R01HL136347-04
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Jun Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,491
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919369

## Citation

> US National Institutes of Health, RePORTER application 9919369, SKca/IKca Channel Activation and Endothelial Protection During Cardiac Surgery (5R01HL136347-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9919369. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*