The prevalence of diabetes and related cardiovascular complications is dramatically increasing worldwide. Patients with diabetes and glucose intolerance carry up to eight times the risk of cardiovascular events compared to nondiabetic individuals and cardiovascular disease is the largest cause of mortality in this population. Although the molecular mechanisms that underlie the abnormal vascular function in diabetic conditions have been examined in in-vitro and in rodent models, their exact role in collateral vessel formation are largely unknown. The validation and extension of these concepts in studies with large animals and patients is lacking. This understanding is an essential prerequisite to their application in humans. We will induce insulin resistance in Yorkshire pigs with high fat feeding creating a model that recreates many of the metabolic, molecular, and microcirculatory abnormalities present in diabetic 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. Our focus is on functional changes in collateral dependent flow, 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), protein O- GlcNAcylation, and insulin signaling. 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.

Public Health Relevance

We do not currently understand the basic mechanisms of collateral vessel formation and the reasons for unsuccessful angiogenic and cell therapy clinical trials in patients with severe coronary artery disease. The proposed integrated approach will result in the identification of crucial pathways, molecular targets, and strategies in pro-angiogenic therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128831-04
Application #
9729053
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Kirby, Ruth
Project Start
2016-04-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
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Potz, Brittany A; Scrimgeour, Laura A; Sabe, Sharif A et al. (2018) Glycogen synthase kinase 3? inhibition reduces mitochondrial oxidative stress in chronic myocardial ischemia. J Thorac Cardiovasc Surg 155:2492-2503
Aldosari, Sarah; Awad, Maan; Harrington, Elizabeth O et al. (2018) Subcellular Reactive Oxygen Species (ROS) in Cardiovascular Pathophysiology. Antioxidants (Basel) 7:
Liu, Yuhong; Cole, Victoria; Lawandy, Isabella et al. (2018) Decreased coronary arteriolar response to KCa channel opener after cardioplegic arrest in diabetic patients. Mol Cell Biochem 445:187-194
Sellke, Nicholas; Gordon, Caroline; Lawandy, Isabella et al. (2018) Impaired coronary contraction to phenylephrine after cardioplegic arrest in diabetic patients. J Surg Res 230:80-86
Sabe, Sharif A; Feng, Jun; Liu, Yuhong et al. (2018) Decreased contractile response of peripheral arterioles to serotonin after CPB in patients with diabetes. Surgery 164:288-293
Potz, Brittany A; Parulkar, Anshul B; Abid, Ruhul M et al. (2017) Novel molecular targets for coronary angiogenesis and ischemic heart disease. Coron Artery Dis 28:605-613
Shafique, Ehtesham; Torina, Anali; Reichert, Karla et al. (2017) Mitochondrial redox plays a critical role in the paradoxical effects of NAPDH oxidase-derived ROS on coronary endothelium. Cardiovasc Res 113:234-246
Potz, Brittany A; Sabe, Ashraf A; Elmadhun, Nassrene Y et al. (2017) Calpain inhibition modulates glycogen synthase kinase 3? pathways in ischemic myocardium: A proteomic and mechanistic analysis. J Thorac Cardiovasc Surg 153:342-357
Potz, Brittany A; Sabe, Ashraf A; Elmadhun, Nassrene Y et al. (2017) Calpain inhibition decreases inflammatory protein expression in vessel walls in a model of chronic myocardial ischemia. Surgery 161:1394-1404

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