Genetic modification of hypertension by sGCa1

Hypertension is an important modifiable risk factor for coronary heart disease, congestive heart failure, stroke, end-stage renal disease, and peripheral vascular disease, but many of the molecular mechanisms and genetic factors underlying the development of the most common forms of human hypertension remain to be defined. Abundant evidence suggests that nitric oxide (NO) and one of its primary targets, the cyclic guanosine monophosphate (cGMP)-generating enzyme soluble guanylate cyclase (sGC), have a critical role in regulating blood pressure. The availability of murine models of hypertension and the revolution in human genetics research (e.g., genome-wide association studies [GWAS]), resulting in the identification of dozens of genetic loci that affect normal variation in blood pressure and susceptibility to hypertension, provide a unique opportunity to dissect the mechanisms by which NO-cGMP signaling regulates blood pressure and to gain important insights into the pathogenesis of hypertension. In this review, we will give an overview of the current knowledge relating to the role of sGC in the regulation of blood pressure, discussing data obtained from genetically modified mouse models as well as from human genetic studies. The NO-sGC-cGMP signaling system The gaseous signaling molecule NO, synthesized by a family of three enzymes referred to as NO synthases (NOSs), is a key regulator of numerous (patho)physiological processes, ranging from neurotransmission to gastrointestinal motility, cardiac function, and blood vessel relaxation. NO has many targets, reacting with a variety of intracellular and extracellular molecules, typically via thiol groups or transition metal centers. In the 1980s, and even before endothelium-derived relaxing factor (EDRF) was identified as NO, EDRF released from endothelial cells was shown to activate the hemoprotein sGC in vascular smooth muscle cells (VSMC). It is now well established that sGC is a major target of NO in the cardiovascular system, eliciting many of NO’s biological actions. sGC functions as an obligate heterodimer, consisting of an α and a β subunit. NO activates sGC by interacting with the prosthetic heme group associated with the sGCβ1 subunit, thereby disrupting the bond between the heme and a nearby histidine (His105). The subsequent conformational change of the heme-binding domain propagates to the catalytic domain, catalyzing the generation of cGMP from GTP, a fast and tightly controlled process. cGMP can then interact with a variety of effector proteins including cGMP-dependent protein kinases (PKGs) and Corresponding author. Tel.: +1 617 643 3493; fax: +1 617 724 7768. [email protected] (E.S. Buys). HHS Public Access Author manuscript Trends Cardiovasc Med. Author manuscript; available in PMC 2016 July 05. Published in final edited form as: Trends Cardiovasc Med. 2013 November ; 23(8): 312–318. doi:10.1016/j.tcm.2013.05.001. A uhor M anscript