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Author(s): Carlos Bernal-Mizrachi [1, 4]; Allison C. Gates [1, 4]; Sherry Weng [1]; Takuji Imamura [2]; Russell H. Knutsen [3]; Pascual DeSantis [1]; Trey Coleman [1]; R. Reid Townsend [1]; [...]

Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator-activated receptor-[alpha] (PPAR-[alpha]) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr[sup.-/-]), with (Ppara[sup.+/+]) or without (Ppara[sup.-/-]) PPAR-[alpha], were treated chronically with dexamethasone. Ppara[sup.+/+], but not Ppara[sup.-/-], mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara[sup.+/+] mice. Adenoviral reconstitution of PPAR-[alpha] in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara[sup.-/-] mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-[alpha] agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-[alpha] as a mechanism underlying glucocorticoid-induced insulin resistance., Author(s): Carlos Bernal-Mizrachi [1, 2]; Sherry Weng [1, 2]; Chu Feng [1, 2]; Brian N Finck [1, 5]; Russell H Knutsen [3]; Teresa C Leone [1, 5]; Trey Coleman [1, [...]

Hyperlipidemia promotes the chronic inflammatory disease atherosclerosis through poorly understood mechanisms. Atherogenic lipoproteins activate platelets, but it is unknown whether platelets contribute to early inflammatory atherosclerotic lesions. To address the role of platelet aggregation in diet-induced vascular disease, we studied [beta]3 integrin-deficient mice (lacking platelet integrin [alpha]11b/[beta]3 and the widely expressed nonplatelet integrin [alpha]v/[beta]3) in two models of atherosclerosis, apolipoprotein E (apoE)-null and low-density lipoprotein receptor (LDLR)-null mice. Unexpectedly, a high-fat, Western-type (but not a low-fat) diet caused death in two-thirds of the [[beta]3.sup.-/-]apo[E.sup.-/-] and half of the [[beta]3.sup.-/-]LDL[R.sup.-/-] mice due to noninfectious pneumonitis. In animals from both models surviving high-fat feeding, pneumonitis was absent, but aortic atherosclerosis was 2- to 6-fold greater in [[beta]3.sup.-/-] compared with [[beta].sup.+/+] littermates. Expression of CD36, CD40L, and CD40 was increased in lungs of [[beta]3.sup.-/-]LDL[R.sup.-/-] mice. Each was also increased in smooth muscle cells cultured from [beta]3-deficient mice and suppressed by retroviral reconstitution of [beta]3. These data show that the platelet defect caused by [alpha]11b[beta]3 deficiency does not impair atherosclerotic lesion initiation. They also suggest that [alpha]v[beta]3 has a suppressive effect on inflammation, the loss of which induces atherogenic mediators that are amplified by diet-induced hyperlipidemia.