Impact of chronic anticholesterol therapy on development of microvascular rarefaction in the metabolic syndrome.
OBJECTIVE
The obese Zucker rat (OZR) model of the metabolic syndrome is partly characterized by moderate hypercholesterolemia, in addition to other contributing comorbidities. Previous results suggest that vascular dysfunction in OZR is associated with chronic reduction in vascular nitric-oxide (NO) bioavailability and chronic inflammation, both frequently associated with hypercholesterolemia. As such, we evaluated the impact of chronic cholesterol-reducing therapy on the development of impaired skeletal muscle arteriolar reactivity and microvessel density in OZR and its impact on chronic inflammation and NO bioavailability.


METHODS
Beginning at seven weeks of age, male OZR were treated with gemfibrozil, probucol, atorvastatin, or simvastatin (in chow) for 10 weeks. Subsequently, plasma and vascular samples were collected for biochemical/molecular analyses, while arteriolar reactivity and microvessel network structure were assessed by using established methodologies after 3, 6, and 10 weeks of drug therapy.


RESULTS
All interventions were equally effective at reducing total cholesterol, although only the statins also blunted the progressive reductions to vascular NO bioavailability, evidenced by greater maintenance of acetylcholine-induced dilator responses, an attenuation of adrenergic constrictor reactivity, and an improvement in agonist-induced NO production. Comparably, while minimal improvements to arteriolar wall mechanics were identified with any of the interventions, chronic statin treatment reduced the rate of microvessel rarefaction in OZR. Associated with these improvements was a striking statin-induced reduction in inflammation in OZR, such that numerous markers of inflammation were correlated with improved microvascular reactivity and density. However, using multivariate discriminant analyses, plasma RANTES (regulated on activation, normal T-cell expressed and secreted), interleukin-10, monocyte chemoattractant protein-1, and tumor necrosis factor alpha were determined to be the strongest contributors to differences between groups, although their relative importance varied with time.


CONCLUSIONS
While the positive impact of chronic statin treatment on vascular outcomes in the metabolic syndrome are independent of changes to total cholesterol, and are more strongly associated with improvements to vascular NO bioavailability and attenuated inflammation, these results provide both a spatial and temporal framework for targeted investigation into mechanistic determinants of vasculopathy in the metabolic syndrome.
Goodwill
Adam G
AG
Department of Physiology and Pharmacology, West Virginia University School ofMedicine, Morgantown, West Virginia, USA.
Frisbee
Stephanie J
SJ
Stapleton
Phoebe A
PA
James
Milinda E
ME
Frisbee
Jefferson C
JC
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001160:Arterioles; D000069059:Atorvastatin; D016207:Cytokines / Q000097:blood; D015248:Gemfibrozil / Q000494:pharmacology / Q000627:therapeutic use; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008833:Microcirculation / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000098:blood supply; D009569:Nitric Oxide / Q000378:metabolism; D011341:Probucol / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
D000924:Anticholesteremic Agents; D016207:Cytokines; D006538:Heptanoic Acids; D011758:Pyrroles; D009569:Nitric Oxide; D000069059:Atorvastatin; D019821:Simvastatin; D011341:Probucol; D015248:Gemfibrozil