Regulation of Gene Expression by Cyclic GMP

Abstract

Abstract-Cyclic GMP, produced in response to nitric oxide and natriuretic peptides, is a key regulator of vascular smooth muscle cell contractility, growth, and differentiation, and is implicated in opposing the pathophysiology of hypertension, cardiac hypertrophy, atherosclerosis, and vascular injury/restenosis. cGMP regulates gene expression both positively and negatively at transcriptional as well as at posttranscriptional levels. cGMP-regulated transcription factors include the cAMP-response element binding protein CREB, the serum response factor SRF, and the nuclear factor of activated T cells NF/AT. cGMP can regulate CREB directly, through phosphorylation by cGMP-dependent protein kinase, or indirectly, through activation of mitogen-activated protein kinase pathways; regulation of SRF and NF/AT by cGMP is indirect, through modulation of RhoA and calcineurin signaling, respectively. Downregulation of the RNA-binding protein HuR by cGMP leads to destabilization of guanylate cyclase mRNA, but this posttranscriptional mechanism may affect many more cGMP-regulated genes. In this review, we discuss the role of cGMP-regulated gene expression in (patho)physiological processes most relevant to the cardiovascular system, such as regulation of vascular tone, cardiac hypertrophy, phenotypic modulation of vascular smooth muscle cells, and regulation of cell proliferation and apoptosis.

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

“…[14][15][16][17]20,[45][46][47] However, the anti-apoptotic and pro-proliferative effects of sildenafil that we found in the corporal smooth muscle do not agree with the fact that cGMP inhibits vascular SMC proliferation. 48,49 Since the effects of BCNR on the corporal histology and pharmacokinetics are the same as those seen in the aged rat, we assume that cGMP effects on corporal SMC may be modulated by some specific features in the corporal SMC themselves or the tissue milieu, that are not operative in the vascular SMC. 12 Another still unresolved question is the role of iNOS induction in corporal atrophy after cavernosal nerve damage.…”

Adrenomedullin, an autocrine/paracrine factor induced by androgen withdrawal, stimulates ‘neuroendocrine phenotype’ in LNCaP prostate tumor cells

“…First, we demonstrate the generation of cGMP and the translocation of cGMP-dependent protein kinases (PKG), the major intracellular cGMP target in many cell types (Pilz and Casteel, 2003), in the nucleus in response to AM. cGMP can regulate transcription factors directly by inducing phosphorylation or by increasing expression of short-lived proteins.…”

“…cGMP can regulate transcription factors directly by inducing phosphorylation or by increasing expression of short-lived proteins. Transcriptions factors whose expression is regulated by cGMP include the AP-1 family proteins c-fos and junB, the early growth response gene Egr-1 and the growth arrestspecific homeobox (Gax) gene (Pilz and Casteel, 2003). Nuclear translocation of PKG has been demonstrated in neuronal cells, neutrophils, macrophages and some embryonal smooth muscle cells (Pilz and Casteel, 2003).…”

“…Transcriptions factors whose expression is regulated by cGMP include the AP-1 family proteins c-fos and junB, the early growth response gene Egr-1 and the growth arrestspecific homeobox (Gax) gene (Pilz and Casteel, 2003). Nuclear translocation of PKG has been demonstrated in neuronal cells, neutrophils, macrophages and some embryonal smooth muscle cells (Pilz and Casteel, 2003). Taken together, our data demonstrate that PKG plays an important role during LNCaP phenotypic modulation in response to AM, positively and negatively regulating gene expression.…”

“…Several groups have shown nuclear translocation of G-kinase I in cGMP-treated cells (Pilz and Casteel, 2003). Accordingly, we examined whether AM induces nuclear translocation of G-kinase Ia and Ib using antibodies specific for each.…”