Cardiovasculardisease(CVD)istheleadingcauseofdeathintheUSA.Increasedlevelsofreactiveoxygen species (ROS) are often associated with microvascular pathology in CVD, causing endothelial dysfunction andcoronaryarterydiseaseandleadingtomyocardialischemiaandinfarction(MI).However,failureoflarge clinical trials using antioxidants in patients with CVD, challenges the prevailing view that ROS production is damaging to the microvasculature. The overarching hypothesis put forth in this proposal is that EC NOX- derived ROS is beneficial for revascularization immediately following myocardial ischemia but becomes detrimentaluponovertheLTduetoincreaseinmitochondrialROS.Thetherapeuticbenefitofinterveningon ROS level is best realized by specific down regulation of mito-ROS in ECs that have been exposed to LT increaseinNOX-ROSsuchasinDM.ThishypothesiswillbefullytestedinvivousingournovelEC-specific transgenic MnSOD (MnSOD-OE) animals and supported using mitochondria-specific nitroxide and nanoparticleantioxidantincoronaryvesselsfromCVDpatientswithDMundergoingcardiacsurgery.
SpecificAim1 :ElucidatethemolecularmechanismsbywhichSTvsLTincreaseinEC-specificNOX-ROS (NOX-OE mouse model) exert differential effects on EC function and angiogenesis and the recovery of the post-infarct ischemic myocardium. We hypothesize that whereas ST NOX-ROS increase induces AMPK?eNOS and AMPK?CPT1-mediated increase in mitochondrial fatty acid oxidation and dNTP synthesis,LTincreaseinNOX-ROSresultsinnitro-tyrosine-inducedinactivationofMnSOD,increaseinmito- ROS,decreaseinmito-membranepotentialanddNTPsynthesisleadingtoreducedECproliferation.
SpecificAim2 :DetermineifEC-specificMnSODoverexpressionprotectsagainstthedetrimentaleffectsof LT exposure of NOX-ROS on vessel density and cardiac functions in post-infarct ischemic myocardium. We hypothesize that SOD-OE will improve post-MI recovery of the cardiac function by reducing mito-ROS and improvingdNTPsynthesis/ECproliferationinLTNOX-OEanimalsandinanimalswithDM.Doubletransgenic NOX-OE:SOD-OEvsNOX-OE,andSOD-OEwithDMwillbeexaminedforpost-MIrecovery.
Specific Aim 3 : Elucidate the effects of mitochondrial-targeted nitroxide antioxidant and SOD biomimetic nanoparticles on post-infarct vessel density and recovery of cardiac function in mice and on chronic myocardialischemiainlargeanimals(swine)withmetabolicsyndrome.
Specific Aim 4 : Determine the effects of mitochondrial-targeted nitroxide antioxidant and SOD biomimetic nanoparticlesonangiogenicpotentialofhumancoronaryvesselsfrompatientswithorwithoutDM.Coronary vessels from atrial tissues of patients (uncontrolled DM HbA1c>8.5, controlled DM HbA1c<7, and non-DM HbA1c<5.5)undergoingcardiacsurgerywillbeexamined.

Public Health Relevance

Thenumberandhealthofthebloodvesselsthatsupplybloodtotheheartarecrucialaftera heart attack (myocardial infarction, MI) as they determine survival and morbidity of the patient. This study will explore a new approach to stimulate blood vessel formation in the heartafterMIbyusingnanoparticle-basedmitochondrialantioxidantinendotheliumthathas beenexposedtochronicallyincreasedoxidantlevelssuchasindiabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL133624-04
Application #
9961390
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chen, Jue
Project Start
2017-08-10
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2020
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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Awad, Maan A; Aldosari, Sarah R; Abid, M Ruhul (2018) Genetic Alterations in Oxidant and Anti-Oxidant Enzymes in the Vascular System. Front Cardiovasc Med 5:107
Scrimgeour, Laura A; Potz, Brittany A; Sellke, Frank W et al. (2017) Continuous Glucose Monitoring in the Cardiac ICU: Current Use and Future Directions. Clin Med Res (N Y) 6:173-176