Guanylyl cyclase can't stand the HETE

Abstract

NITRIC OXIDE (NO)-sensitive isoforms of heterodimeric guanylyl cyclase [␣ 1 ␤ 1 -and ␣ 2 ␤ 1 -soluble guanylyl cyclases (sGC)], extend an umbrella of protection throughout the cardiovascular system, with wide-ranging effects on local blood flow, platelet and leukocyte reactivity, vessel morphology, and cardiac structure and function (5, 10). Consequently, dysfunctional sGC signaling precipitates cardiovascular disease in an analogous manner to deficits in NO bioactivity, perhaps illustrated most tangibly in the context of human pathophysiology by genomewide association studies (GWAS) identifying mutations in the GUCY1A3 and GUCY1B3 genes, which encode the two principal subunits of the enzyme (sGC␣ 1 and sGC␤ 1 , respectively), to associate with a hypertensive phenotype (6). Preclinical models have also borne out a clear relationship between sGC activity, local vascular tone, and systemic blood pressure. This is best illustrated by the hypertensive phenotype in mice with genetic deletions of either sGC␣ 1 or sGC␤ 1 (3,8,9,17,19). Interestingly, the sGC␣ 1 and sGC␤ 1 null mice exhibit a strainand sex-specific rise in blood pressure (3,17), and this phenomenon has shed light on mechanisms critical to the vasoprotective functions of NO-sGC signaling, both in terms of endothelium-dependent dilatation and more global effects on neurohormonal axes. For example, the sex difference in response to sGC deletion dovetails well with studies revealing a marked increase in blood pressure in male endothelial NO synthase (eNOS)/cyclooxygenase-1 double knockout (KO) mice, which are unable to synthesize two principal endotheliumderived vasodilators, NO and prostacyclin (14). In these animals, endothelium-dependent relaxation is restricted to that provided by hyperpolarization pathways, i.e., endotheliumdependent hyperpolarization (EDH), which are upregulated by female sex steroids (20); in contrast, the predominant endothelium-derived dilator in males is NO, thereby explaining why deletion of eNOS or sGC results in raised blood pressure. Consequently, sGC KO mice are good models with which to ascertain the role of male sex steroids, primarily testosterone, in the development of hypertension. For example, previous studies capitalizing on the sGC␣ 1 KO mice have revealed an androgen-driven increase in renin activity that contributes to the hypertensive phenotype in these animals (2, 3).In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Dordea et al. (5a) provide a timely and thought-provoking report identifying a further pathway upregulated by sGC␣ 1 deletion that underlies the development of hypertension in a sex-specific manner. Via linkage analysis, the authors identified a quantitative trait locus that associates with elevated blood pressure in male 129S6 mice that is shared by neither counterparts on a C57BL6 background nor female animals of either strain. In-depth analysis revealed that this region encodes a cluster of the cytochrome P-450 (Cyp) 4a isoforms, including Cyp4a10, Cyp4a12, and Cy...