Cynthia Meininger

Personal Information
Title Professor
Expertise Cardiovascular
Institution Texas A&M Health Science Center
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Grants/SubContracts 1
Progress Reports 1
Publications 1
Protocols 0
Committees 2

BH4-Loaded Nanoparticles for Diabetes-Associated Cardiovascular Disease
A deficiency of tetrahydrobiopterin (BH4), a critical cofactor for endothelial nitric oxide synthase, is a majorfactor responsible for vascular dysfunction in diabetes. Our overall goal is to develop an effective therapeuticregimen to augment BH4 levels in endothelial cells in order to increase their ability to synthesize nitric oxide,thereby delaying/attenuating development of cardiovascular disease. We previously showed that BH4encapsulated in injectable polymer-based nanoparticles significantly improved vascular function in diabeticrats. More recently, we synthesized solid lipid nanoparticles (SLNs) containing BH4 that can be swallowed.Our objective was to deliver BH4 to the systemic circulation via selective uptake and transit of SLNs by thegastrointestinal lymphatics, initially bypassing the liver and therefore effectively making more BH4 availableto extrahepatic tissues. We hypothesize that BH4-loaded SLNs, delivered via oral administration, willdelay/attenuate the well-characterized atherogenesis noted in an ApoE-deficient mouse that is also insulindeficient. Two aims are proposed: (1) Determine the optimal treatment schedule for orally administered BH4-loaded SLNs to provide long-term reversal of endothelial dysfunction in a model of diabetes-associatedatherosclerosis, and (2) Demonstrate that orally administered BH4-loaded SLNs reduce the atherosclerosisassociated with diabetes. Vascular function, endothelial BH4 levels, atherosclerotic lesion size, inflammatorycell infiltration, adhesion molecule expression, as well as pharmacokinetic, metabolic and toxicity parameterswill be assessed. Using SLNs allows us to encapsulate BH4, protecting it from oxidation as well asimmediate metabolism in the liver, while delivering this critical cofactor to endothelial cells in a sustainedfashion to attenuate cardiovascular disease associated with diabetes. Upregulation of BH4 levels inoxidatively damaged endothelial cells will not only reverse dysfunction caused by disease but will alsoprotect endothelial cells from future damage/dysfunction by increasing their endogenous pool of antioxidants.Finally, oral delivery of BH4-loaded SLNs has obvious advantages in terms of patient compliance for chronictreatment of vascular complications associated with diabetes.

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 PublicationAltmetricsSubmitted ByPubMed IDStatus

Year: 2016; Items: 1

Mast cells and histamine are triggering the NF-?B-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation.
Nizamutdinova IT, Dusio GF, Gasheva OY, Skoog H, Tobin R, Peddaboina C, Meininger CJ, Zawieja DC, Newell-Rogers MK, Gashev AA
Aging, 2016 (8), 3065 - 3090
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