Targeting Mas Receptor for Diabetic Vascular Disease in Older Adults Abstract Prevalence of diabetes is high among older adults and is expected to rise, and diabetes increases risk for cardiovascular disease. Accumulated evidence suggests that bone marrow-derived progenitor cells maintain vascular health and promote rapid repair following vascular injury. This innate vascular protection is diminished with aging and diabetes due to impaired mobilization of EPCs from bone marrow into circulation and decreased ability to repair damaged blood vessels. Therefore approaches that preserve EPC mobilization and function will prevent the development of vascular disease in older adults with diabetes. We hypothesize that the Mas receptor, the functional mediator of the vasoprotective axis of renin angiotensin system, confers mobilization and reparative functions in EPCs and that early intervention with MasR activation would preserve innate vasoprotection and prevents the development of vascular disease with aging and diabetes. This hypothesis is based on our novel findings that showed angiotensin converting enzyme-2 that generates heptapeptide angiotensin (Ang)-(1-7), the endogenous activator of MasR, is down-regulated with aging and diabetes. Importantly, genetic deficiency of MasR (MasR-KO) precipitates EPC moblilopathy and vasoreparative dysfunction following ischemic vascular injury, similar to aging and diabetes.
Three aims are proposed to test the hypothesis.
Aim -1 will define the role of MasR in the mobilization and vasoreparative functions of EPCs by using radiation chimeras of MasR-KO mice.
Aim -2 will test the beneficial effects of long- term activation of MasR on the development of vasoreparative dysfunction with aging and diabetes. This will be accomplished by overexpressing Ang-(1-7) by adenoviral or nonviral approaches. We will test if the overexpression of Ang-(1-7) will reverse the vasoreparative dysfunction in CD34+EPCs derived from older adults with diabetes. Therefore Aim-2 will provide the proof-of-concept for the translational potential of the study.
Aim 3 will demonstrate the involvement of novel pathways that mediate the reversal of mobilization and vasoreparative dysfunctions in diabetic EPCs by MasR activation, Slit/Robo/ROCK pathway and TERT/mitoROS/NO pathway, respectively. Overall, this study will provide a novel mechanism-based pharmacological approach for reversal as well as prevention of diabetic vascular disease in older adults with diabetes.

Public Health Relevance

Targeting Mas Receptor for Diabetic Vascular Disease in Older Adults Narrative This proposal tests the hypothesis that MasR activation is a promising approach for prevention of the development of vascular disease in older adults with diabetes. Prevalence of diabetes is high among older adults and is expected to rise, and diabetes increases risk for cardiovascular disease. Accumulated evidence suggests that bone marrow-derived progenitor cells maintain vascular health and promote rapid repair following vascular injury. This innate vascular protection is diminished with aging and diabetes due to impaired mobilization of EPCs from bone marrow into circulation and decreased ability to repair damaged blood vessels. Therefore discovery of novel mechanism-based approaches that preserve EPC mobilization and function are needed to prevent the development of vascular disease with aging and diabetes. Our novel hypothesis is based on recent findings that showed evidence for the reduced activity of vasoprotective axis of renin angiotensin system with aging and diabetes resulting in lack of MasR activation by its ligand, angiotensin (Ang)-(1-7). Ang- (1-7) treatment reversed EPC dysfunctions in diabetic mice and importantly, genetic deficiency of MasR (MasR- KO) precipitated vasoreparative dysfunctions similar to aging and diabetes. Three aims are proposed to test the hypothesis. Aim-1 will define the role of MasR in the mobilization and vasoreparative functions of EPCs by using radiation chimeras of MasR-KO mice. We will determine the vasculogenic and paracrine angiogenic functions of EPCs that are deficient of MasR. Aim-2 will test the beneficial effects of long-term activation of MasR on the development of vasoreparative dysfunction with aging and diabetes. This will be accomplished by overexpressing Ang-(1-7) by adenoviral or nonviral approaches. We will test if the overexpression of Ang-(1-7) will reverse the vasoreparative dysfunction in CD34+EPCs derived from older adults with diabetes. Therefore Aim-2 will provide the proof-of-concept for the translational potential of the study. Aim 3 will demonstrate the involvement of novel pathways that mediate the reversal of mobilization and vasoreparative dysfunctions in diabetic EPCs by MasR activation, Slit/Robo/ROCK pathway and TERT/mitoROS/NO pathway, respectively. Overall, this study will provide a novel mechanism-based pharmacological approach for reversal as well as prevention of diabetic vascular disease in older adults with diabetes. MasR activators are currently in clinical trials for cardiopulmonary diseases therefore the outcomes of this proposal can be rapidly transitioned towards clinical evaluation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG056881-03
Application #
9698865
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Kerr, Candace L
Project Start
2017-09-15
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
North Dakota State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
803882299
City
Fargo
State
ND
Country
United States
Zip Code
58108