Hypercholesterolemia and Human Skin Blood Flow

Project: Research project

Description

DESCRIPTION (provided by applicant): The cutaneous circulation is an accessible, representative vascular bed for in vivo examination of mechanisms that contribute to vascular dysfunction. This proposal is a logical extension of our previous work investigating the neurovascular mechanisms underlying age-related changes in the control of skin blood flow. The proposed studies expand our previous research to examine cutaneous vasodilatory (VD) signaling mechanisms in a hypercholesterolemic (HC) population. Impaired VD signaling with HC is characterized by an increase in oxidant stress coupled with the loss of endothelial nitric oxide (NO); together these events contribute to endothelial dysfunction associated with the pathogenesis of atherosclerosis. The precise mechanisms mediating decreased endothelial NO remain unclear. Putative sites through which NO may be decreased with HC include 1) oxidized low density lipoprotein (ox-LDL)-induced upregulation of vascular arginase activity, which preferentially metabolizes the common NO-synthase (NOS) substrate L- arginine (L-arg) to L-ornithine and urea and 2) endothelial (e)NOS uncoupling where eNOS contributes to increased oxidant stress by producing superoxide as a result of substrate (L-arg) or essential cofactor (tetrahydrobiopterin) deficiency. Additionally, there is a mechanistic link between ox-LDL-induced augmented vascular arginase activity and the pathogenesis of atherosclerosis through an increase in the polyamine and proline precursor L-ornithine which contributes to intimal thickening. To this end, the proposed investigations will systematically explore mechanisms affecting impaired NO- dependent cutaneous VD with HC using state-of-the-art in vivo skin specific techniques (local heating and intradermal microdialysis) paired with classic in vitro biochemical analysis of cutaneous biopsies. Specific Aims 1 and 2 will mechanistically examine the roles of arginase, and oxidant stress in the context of eNOS uncoupling, respectively, to clarify their contributions to VD dysfunction with HC compared to an age- matched normocholesterolemic control group. Specific Aim 3 will complement Aims 1 and 2 with in vitro biochemical analysis of eNOS and arginase gene expression, enzyme activity, and protein concentration. Specific Aim 4 examines the mechanisms investigated in Aims 1-3 before and after a statin therapy intervention with atrovastatin.
StatusFinished
Effective start/end date9/7/076/30/13

Funding

  • National Institutes of Health: $353,417.00
  • National Institutes of Health: $352,198.00
  • National Institutes of Health: $354,060.00
  • National Institutes of Health: $354,651.00
  • National Institutes of Health: $360,932.00

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Hypercholesterolemia
Arginase
Skin
Blood Vessels
Nitric Oxide
Oxidants
Ornithine
Nitric Oxide Synthase
Arginine
Atherosclerosis
Complement C2
Tunica Intima
Complement C1
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Phenylketonurias
Microdialysis
Polyamines
Proline
Superoxides
Heating