CALL FOR PAPERS Pathophysiology of Hypertension Role of macrophage PPAR in experimental hypertension

Kriska T, Cepura C, Gauthier KM, Campbell WB. Role of macrophage PPAR in experimental hypertension. Am J Physiol Heart Circ Physiol 306: H26–H32, 2014. First published October 25, 2013; doi:10.1152/ajpheart.00287.2013.—Targeted disruption of the Alox15 gene makes mice resistant to angiotensin II-, DOCA/salt-, and N -nitroL-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) agonists, we hypothesized that activation of macrophage PPAR is the key step in Alox15 mediation of hypertension. Thioglycollate, used for macrophage elicitation, selectively upregulated PPAR 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 was further specified by using the selective PPAR antagonist GW9662. WT mice treated with 50 g/kg daily dose of GW9662 for 12 days became resistant to L-NAME-induced hypertension. The PPAR antagonist treatment also prevented L-NAME-induced hypertension in thioglycollate-injected Alox15 / mice, indicating a PPAR -mediated effect in macrophage elicitation and the resultant hypertension. These results indicate a regulatory role for macrophage-localized PPAR in L-NAME-induced experimental hypertension.