# Surgical Cardioprotection Through BKCa-Dependent Modulation of Mitochondrial Supercomplexes

> **NIH NIH R01** · UNIVERSITY OF RHODE ISLAND · 2020 · $386,250

## Abstract

Abstract: Myocardial stunning is present following ischemic insults associated with elective cardiac arrest
during the majority of cardiac surgeries and significantly contributes to patient morbidity and mortality. During
surgery, cardioplegia solutions provide significant cardioprotection from what would otherwise be lethal
ischemic injury. However, there is still significant injury during these procedures to the myocardial tissue. This
grant seeks to determine 1) the mechanism of cardioprotection associated with activation of a mitochondrial K+
channel (BKCa) and if driving activation will mitigate myocardial stunning associated with ischemic insults
during cardiac surgery, and 2) if novel strategies to promote mitochondrial reorganization and function are
viable therapeutic strategies. The mechanism of mitochondrial K+-mediated cardioprotection is currently
unknown. We present preliminary data, that activators or overexpression of active BKCa channels improves LV
function and hemodynamics following ischemic injury associated with isolated cell and animal models of
cardioplegic arrest. We also present novel evidence that BKCa activation may improve cardioprotection
through alterations in mitochondrial structural proteins and increase the formation of electron transport chain
supercomplexes, thereby providing more efficient cellular respiration, and decreased reactive oxygen species
generation. The current proposal will investigate the novel mechanism of mitochondrial K+ mediated
cardioprotection with specific focus on K+-dependent modulation of mitochondrial cristae junction protein
complexes, enhanced mitochondrial supercomplex formation, improved respiration, and decreased ROS. In
addition, there is a strong effort towards translation of these studies, with verification of the relevant findings in
a pre-clinical large animal model of CP/CPB and definition of the proposed pathological insult in human heart
tissue before and after cardiac surgery. The potential elucidation of this mechanism will have implication for
ischemic injury and numerous other myocardial metabolic alterations. The proposal is in three specific aims: I)
Determine the role of respiratory supercomplexes and cristae remodeling in BKCa-mediated enhanced
myocardial protection in vitro. The mechanism of BKCa-mediated cardioprotection (respiration, respiratory
supercomplex formation, ATP generation, superoxide production, etc...) will be evaluated using isolated
myocytes with genetic and pharmacologic manipulation. II) Determine if BKCa-mediated supercomplex
formation enhances cardiac contractile function and cardioprotection following cardioplegic arrest and
reperfusion ex vivo. Mouse isolated hearts will be subjected to ischemic cardioplegic arrest and reperfusion
with and without BKCa channel pharmacologic activators and genetic interventions. III) Determine if similar
pathological mechanisms are present in humans undergoing CP/CPB using myocardial tissue samples before
and a...

## Key facts

- **NIH application ID:** 9960559
- **Project number:** 5R01HL135236-04
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** Richard T Clements
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2018-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960559

## Citation

> US National Institutes of Health, RePORTER application 9960559, Surgical Cardioprotection Through BKCa-Dependent Modulation of Mitochondrial Supercomplexes (5R01HL135236-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9960559. Licensed CC0.

---

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