PROJECT SUMMARY
Coronary microvascular dysfunction (CMD) is linked to coronary artery disease (CAD), diabetic cardiomyopathy,
and HFpEF (heart failure with preserved ejection fraction). In healthy adults, nitric oxide (NO) mediates
endothelium-dependent dilation, whereas hydrogen peroxide (H2O2) is the principal endothelial dilator in patients
with CAD. Such a transition might be an early pathogenic step in the progression of CAD, but little is known
about the mechanisms underlying this switch, and whether under chronic conditions the switch can be reversed.
This proposal addresses the mechanisms underlying the NO to H2O2 switch by using preclinical models that
recapitulate the clinical CAD observations by the Gutterman group. We hypothesize that “normal” coronary
microvascular function (restoring endothelial-dependent dilation) can be restored by modulating
microRNA-21 (miR-21) expression and that miR-21 regulates endothelial (EC) and endothelial progenitor
cell (EPC) function in diabetes. To test this hypothesis, we proposed three specific aims that utilize genetic
miR-21 deletion strategies to address the impact of the miR-21 deficiency in a HFHS model of diabetes. Aim 1
addresses key aspects of EPC function and signaling pathways via single cell RNA sequencing. Aim 2 utilizes
intramyocardial transplantation EPCs and myocardial blood flow measurements to determine if EPCs can
reverse the NO to H2O2 switch. Aim 3 investigates the role of miR-21 specifically in ECs to determine the impact
on preventing / reversing the NO to H2O2 switch and assesses vasomotor function and myocardial blood flow in
diabetes. Overall, the current proposal merges vascular physiological concepts and methodologies with state-
of-the genetic tools and instrumentation to gain novel insight into the mechanisms of CMD in diabetes by studying
the EPC-EC-microvascular function axis and the physiological and pathological consequences surrounding miR-
21.
To ensure scientific rigor, quality of research, and career development, the training plan laid out for this fellowship
entails a combination of technical skill acquisition and regular scientific engagement among peers, colleagues,
and professors to facilitate critical thinking and scientific communication skills. The research environment at
Northeast Ohio Medical University can be described as highly collaborative, ethical, and proficient.