cyclic-gmp and Hyperlipoproteinemia-Type-II

The discovery of nitric oxide (NO) as an activator of soluble guanylate cyclase (sGC) has stimulated extensive research on the NO-sGC-3':5'-cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinase (PKG) pathway. However, the restricted localization of pathway components and the lack of information on PKG substrates have hindered research seeking to examine the physiological roles of the NO-sGC-cGMP-PKG pathway. An excellent substrate for PKG is the G-substrate, which was originally discovered in the cerebellum. The role of G-substrate in the cerebellum and other brain structures has been revealed in recent years. This review discusses the relationship between the G-substrate and other components of the NO-sGC-cGMP-PKG pathway and describes the characteristics of the G-substrate gene and protein related to diseases. Finally, we discuss the physiological role of G-substrate in the cerebellum, where it regulates cerebellum-dependent long-term memory, and its role in the ventral tegmental area and retina, where it acts as an effective neuroprotectant.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aging; Amacrine Cells; Amino Acid Sequence; Animals; Central Nervous System Diseases; Cerebellum; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide-Gated Cation Channels; Gene Expression Regulation, Developmental; Guanylate Cyclase; Humans; Hyperlipoproteinemia Type II; Long-Term Synaptic Depression; Memory, Long-Term; Molecular Sequence Data; Nerve Tissue Proteins; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphorylation; Protein Isoforms; Protein Processing, Post-Translational; Receptors, Cytoplasmic and Nuclear; Second Messenger Systems; Sequence Alignment; Sequence Homology, Amino Acid; Soluble Guanylyl Cyclase; Ventral Tegmental Area; Vocalization, Animal

Increased production of reactive oxygen species and loss of endothelial nitric oxide (NO) bioactivity are key features of vascular disease states such as atherosclerosis. Tetrahydrobiopterin (BH4) is a required cofactor for NO synthesis by endothelial nitric oxide synthase (eNOS); pharmacologic studies suggest that reduced BH4 availability may be an important mediator of endothelial dysfunction in atherosclerosis. We aimed to investigate the importance of endothelial BH4 availability in atherosclerosis using a transgenic mouse model with endothelial-targeted overexpression of the rate-limiting enzyme in BH4 synthesis, GTP-cyclohydrolase I (GTPCH).. Transgenic mice were crossed into an ApoE knockout (ApoE-KO) background and fed a high-fat diet for 16 weeks. Compared with ApoE-KO controls, transgenic mice (ApoE-KO/GCH-Tg) had higher aortic BH4 levels, reduced endothelial superoxide production and eNOS uncoupling, increased cGMP levels, and preserved NO-mediated endothelium dependent vasorelaxations. Furthermore, aortic root atherosclerotic plaque was significantly reduced in ApoE-KO/GCH-Tg mice compared with ApoE-KO controls.. These findings indicate that BH4 availability is a critical determinant of eNOS regulation in atherosclerosis and is a rational therapeutic target to restore NO-mediated endothelial function and reduce disease progression.

Topics: Animals; Aorta; Aortic Diseases; Apolipoproteins E; Arteriosclerosis; Biopterins; Coenzymes; Crosses, Genetic; Cyclic GMP; Diet, Atherogenic; Endothelium, Vascular; GTP Cyclohydrolase; Humans; Hyperlipoproteinemia Type II; Hyperlipoproteinemia Type IV; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nitric Oxide; Organ Specificity; Receptor, TIE-2; Recombinant Fusion Proteins; Superoxides; Vasodilation

The negative charges of dextran-sulfate (DS) used for low-density-lipoprotein (LDL) apheresis initiate the intrinsic coagulation pathway in which plasma kallikrein acts on the high-molecular-weight kininogen to produce large amounts of bradykinin. This study was undertaken to assess whether bradykinin generated during DS LDL apheresis has any physiologic effects in vivo. The plasma levels of bradykinin, prostaglandins and cyclic guanosine monophosphate (cGMP) were compared. when either of two anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. Although anticoagulative action by NM depends on the inhibition of thrombin activity this substance also inhibits the activity of plasma kallikrein. During apheresis using heparin, the plasma levels of prostaglandin E2 (PGE2) increased significantly (5.6 +/- 1.2 (mean +/- SE, n = 4) pg/ml before apheresis and 33.4 +/- 13.2 after apheresis, p < 0.05) in association with an increase in bradykinin levels (17.9 +/- 2.6 pg/ml before apheresis and 470 +/- 135 after apheresis, p < 0.01). Interestingly, these changes were suppressed during apheresis using NM. There were no appreciable changes in cGMP during DS LDL apheresis with either of the anticoagulants. This finding suggests that bradykinin generated during apheresis has some pathophysiological effects via activation of the prostaglandin system. Our results support the view that in patients taking angiotensin-converting-enzyme inhibitors, the anaphylactoid reaction occurring during apheresis may be caused by an excessive rise in the bradykinin levels.

Topics: 6-Ketoprostaglandin F1 alpha; Anticoagulants; Benzamidines; Blood Component Removal; Bradykinin; Cyclic GMP; Dextran Sulfate; Dinoprostone; Factor XII; Guanidines; Heparin; Humans; Hyperlipoproteinemia Type II; Kallikreins; Kininogens; Lipoproteins, LDL; Male; Middle Aged; Prekallikrein