Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The type I cGMP-dependent protein kinase (cGK) is one of the major pathways for the cGMP cascade and has been demonstrated to inhibit platelet aggregation, relax smooth muscle cells, and control cardiocyte contractility. There are two subtypes of the type I cGK, cGKIalpha and cGKIbeta. The former is more sensitive to cGMP than the latter. In humans, cGKIbeta cDNA was isolated, but the full structure and tissue-specific gene expression of cGKIalpha have not been determined. The significance of cGK in human cardiovascular diseases has not been investigated at the molecular level. In the present study, we isolated the full-length human CGKIalpha cDNA (-36 to +2177; the translation start site: +1) enclosing the 671-amino acid protein. Nucleotides +267 to +2177 of the isolated cDNA were identical to the corresponding nucleotides of human cGKIbeta cDNA. Southern blot analysis suggested that human cGKIalpha and cGKIbeta are generated by alternative splicing of a single gene assigned to chromosome 10. By Northern blot analysis, we detected abundant human cGKIalpha mRNA (7.0 kb) in the aorta, heart, kidneys, and adrenals. In contrast, human cGKIbeta mRNA (7.0 kb) was detected abundantly only in the uterus. In cultured vascular smooth muscle cells, the type I cGK mRNA concentration was reduced to 10% of the basal level by 4 x 10(-10) mol/L platelet-derived growth factor. Angiotensin II (10(-8) mol/L), transforming growth factor-beta (4 x 10(-11) mol/L), and tumor necrosis factor-alpha (6 x 10(-6) mol/L) also exhibited an inhibitory effect on type I cGK gene expression. These findings suggest a pathophysiological implication of the type I cGK in cardiovascular diseases, including hypertension and atherosclerosis.
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PMID:cDNA cloning and gene expression of human type Ialpha cGMP-dependent protein kinase. 861 2

Excessive transforming growth factor-beta (TGF-beta) activity in hyperglycemia contributes to the development of diabetic nephropathy. Glucose stimulation of TGF-beta activity and matrix synthesis are dependent on autocrine thrombospondin 1 (TSP1) to convert latent TGF-beta to its biologically active form. The mechanisms by which glucose regulates TSP1 are not known. High glucose inhibits nitric oxide (NO) bioavailability and decreased NO increases TGF-beta activity and extracellular matrix accumulation. Yet, the impact of NO signaling on TSP1 activation of TGF-beta is unknown. We tested the role of NO signaling in the regulation of TSP1 expression and TSP1-dependent TGF-beta activity in rat mesangial cells exposed to high glucose. On exposure to 30 mm glucose, NO accumulation in the conditioned media and intracellular cGMP levels were significantly decreased. The addition of an NO donor prevented the glucose-dependent increase in TSP1 mRNA, protein, and TGF-beta bioactivity. The effects of the NO donor were blocked by ODQ (a soluble guanylate cyclase inhibitor) or Rp-8-pCPT-cGMPS (an inhibitor of cGMP-dependent protein kinase). These effects of high glucose were also reversed by the nitric-oxide synthase cofactor tetrahyrobiopterin (BH(4)). These results show that high glucose mediates increases in TSP1 expression and TSP1-dependent TGF-beta bioactivity through down-modulation of NO-cGMP-dependent protein kinase signaling.
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PMID:Nitric oxide and cGMP-dependent protein kinase regulation of glucose-mediated thrombospondin 1-dependent transforming growth factor-beta activation in mesangial cells. 1178 17

Nitric oxide signaling has an important role in regulating pulmonary development and function. Expression of soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI), both critical mediators of nitric oxide (NO) signaling, is diminished in the injured newborn lung through unknown mechanisms. Recent studies suggest that excessive transforming growth factor-beta (TGF-beta) activity inhibits injured newborn lung development. To explore mechanisms that regulate pulmonary NO signaling, we tested whether TGF-beta decreases sGC and PKGI expression in the injured developing lung and pulmonary vascular smooth muscle cells (SMC). We found that chronic oxygen-induced lung injury decreased pulmonary sGCalpha(1) and PKGI immunoreactivity in mouse pups and that exposure to a TGF-beta-neutralizing antibody prevented this reduction of sGC and PKGI protein expression. In addition, TGF-beta(1) decreased expression of NO signaling enzymes in freshly isolated pulmonary microvascular SMC/myofibroblasts, suggesting that TGF-beta has a direct role in modulating NO signaling in the pup lung. Moreover, TGF-beta(1) decreased sGC and PKGI expression in pulmonary artery and aortic SMC from adult rats and mice, suggesting a general role for TGF-beta in modulating NO signaling in vascular SMC. Although other cytokines decrease sGC mRNA stability, TGF-beta did not modulate sGCalpha(1) or PKGIbeta mRNA turnover in vascular SMC. These studies indicate for the first time that TGF-beta decreases NO signaling enzyme expression in the injured developing lung and pulmonary vascular SMC. Moreover, they suggest that TGF-beta-neutralizing molecules might counteract the effects of injury on NO signaling in the newborn lung.
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PMID:Transforming growth factor-beta modulates the expression of nitric oxide signaling enzymes in the injured developing lung and in vascular smooth muscle cells. 2002 76