# Vascular Dysfunction in Myocardial Ischemia and Metabolic Syndrome

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2022 · $818,360

## Abstract

Project Summary/Abstract
Despite robust evidence that metabolic syndrome (MetS) is associated with an increased risk of cardiovascular
disease (CVD), the mechanism of this increased risk remains obscure. In particular, obesity, hypertension, and
diabetes (all components of MetS) have been reported in this population as primary risk factors for cardiac events
with the leading cause of mortality. Although the molecular mechanisms underlying abnormal cardiovascular
function have been investigated in in-vitro and rodent models under MetS conditions, their exact role in the
formation of cardiac collateral vessels is largely unknown. There is a lack of evidence and extension in
experiments with large animals and patients of these principles. This awareness is an essential prerequisite for
their human application.
We will induce MetS with insulin resistance in male intact Yorkshire pigs with high fat feeding a model that
recreates many of the metabolic, molecular, and microcirculatory abnormalities present in MetS patients. Our
prior studies and preliminary data show that porcine models of diabetes closely resemble the disease in patients
and lead to diminish myocardial and vascular regeneration and we will use the model in this proposal. In order
to adjust the blood glucose level, we will treat pigs with sitagliptin and canagliflozin and compare the answer to
lean diet controls. In this proposal we will concentrate on the effects of SGLT1 inhibition on collateral
development and the metabolic, molecular, and microcirculatory abnormalities present in patients with overt
diabetes and metabolic syndrome. Our focus is on functional changes in collateral dependent myocardial
perfusion, vascular density, and microvascular function together with key molecular events involved in the altered
collateral formation process in vivo.
We will use mechanistic approach to understand molecular interactions in pathways and networks and functional
attributes to unravel the molecular base of impaired angiogenesis in diabetes. Our published and preliminary
data suggests for involvement and functional interactions in the hexosamine biosynthetic pathway (HBP), citric
acid cycle (CAC), insulin signaling, and protein O-GlcNAcylation.
The proposed integrated approach will result in the identification of crucial pathways, molecular targets, and
strategies in pro-angiogenic therapy and cell-based regeneration and tissue engineering, the clinical importance
of this proposal is evident. The use of a large animal model with type 2 diabetes and metabolic syndrome is a
strong aspect of the project.

## Key facts

- **NIH application ID:** 10520236
- **Project number:** 2R01HL128831-05A1
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Frank W Sellke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $818,360
- **Award type:** 2
- **Project period:** 2016-04-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520236

## Citation

> US National Institutes of Health, RePORTER application 10520236, Vascular Dysfunction in Myocardial Ischemia and Metabolic Syndrome (2R01HL128831-05A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10520236. Licensed CC0.

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