Role of macrophage PPARγ in experimental hypertension.

Targeted disruption of the Alox15 gene makes mice resistant to angiotensin II-, DOCA/salt-, and N-omega-nitro-L-arginine methyl ester (L-NAME)-induced experimental hypertension. Macrophages, a primary source of Alox15, are facilitating this resistance, but the underlying mechanism is not known. Because Alox15 metabolites are peroxisome proliferator-activated receptor (PPAR)gamma agonists, we hypothesized that activation of macrophage PPAR gamma is the key step in Alox15 mediation of hypertension. Thioglycollate, used for macrophage elicitation, selectively upregulated PPAR gamma and its target gene CD36 in peritoneal macrophages of both wild-type (WT) and Alox15(-/-) mice. Moreover, thioglycollate-injected Alox15(-/-) mice became hypertensive upon L-NAME treatment. A similar hypertensive effect was observed with adoptive transfer of thioglycollate-elicited Alox15(-/-) macrophages into Alox15(-/-) recipient mice. The role of PPAR gamma was further specified by using the selective PPAR gamma antagonist GW9662. WT mice treated with 50 mu g/kg daily dose of GW9662 for 12 days became resistant to L-NAME-induced hypertension. The PPAR gamma antagonist treatment also prevented L-NAME-induced hypertension in thioglycollate-injected Alox15(-/-) mice, indicating a PPAR gamma-mediated effect in macrophage elicitation and the resultant hypertension. These results indicate a regulatory role for macrophage-localized PPAR gamma in L-NAME-induced experimental hypertension.