Physiological and pathological effects of complete sGC deletion
© Friebe et al; licensee BioMed Central Ltd. 2007
Published: 25 July 2007
By catalyzing the production of the intracellular signaling molecule cGMP NO-sensitive guanylyl cyclase (NO-GC), as the major receptor for NO, has a key function within the NO/cGMP cascade. The pharmacological importance of the enzyme is reflected by NO donors used for the therapy of coronary heart disease. NO-GC is made up of one β subunit and one α subunit. As there are two α subunits (α1 and α2), two different GC isoforms are known to exist (α1β1 and α2β1). In the cardiovascular system, vasorelaxation and inhibition of platelet aggregation are mediated by the α1β1 GC. As the α2 subunit is mainly found in nerve cells of the CNS, the α2β1 heterodimer is believed to participate in synaptic plasticity. The role of NO-GC in the gastrointestinal tract is still unclear. NO is contributing to non-adrenergic non-cholinergic (NANC) relaxation of gastrointestinal smooth muscle.
Using mice deficient in the β1 subunit we investigated the role of NO-GC in vascular and intestinal tissues. These mice do not express any of the α subunits and reveal no detectable cGMP synthesis upon NO stimulation. Thus mice lacking the β subunit are in fact total NO-GC knock out mice. Whereas mice heterozygous for the β1 subunit of NO-GC were phenotypically undistinguishable from WT, homozygous GC-KO mice died prematurely. 3-week-old homozygous GC-KO mice exhibit considerable growth retardation shown by a 40% reduced body weight. KO mice surviving until day 18+ are hypertensive and die from gastrointestinal dysmotility leading to ileus and perforation. By substituting normal rodent chow with fiber-free diet we were able to rescue GC-KO mice.
In order to find out the relative contribution of smooth muscle cells to the GC-KO phenotype we are currently investigating smooth muscle specific GC-KO mice (SMKO). Tamoxifen was used for induction of the tissue-specific KO. SMKO mice do not reveal the reduced life expectancy of total GC-KO mice. However, tamoxifen-injected SMKO animals develop hypertension within several weeks. This model of a slowly developing hypertension further underlines the importance of constitutively released endothelial NO as major regulator of blood pressure.
This article is published under license to BioMed Central Ltd.