cyclic-gmp and Metabolic-Diseases

The intracellular nucleotide cyclic guanosine monophosphate (cGMP) is found in many human organ tissues. Its concentration increases in response to the activation of receptor enzymes called guanylyl cyclases (GCs). Different ligands bind GCs, generating the second messenger cGMP, which in turn leads to a variety of biological actions. A deficit or dysfunction of this pathway at the cardiac, vascular, and renal levels manifests in cardiovascular diseases such as heart failure, arterial hypertension, and pulmonary arterial hypertension. An impairment of the cGMP pathway also may be involved in the pathogenesis of obesity as well as dementia. Therefore, agents enhancing the generation of cGMP for the treatment of these conditions have been intensively studied. Some have already been approved, and others are currently under investigation. This review discusses the potential of novel drugs directly or indirectly targeting cGMP as well as the progress of research to date.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzoates; Cardiovascular Diseases; Cyclic GMP; Enzyme Activators; Guanylate Cyclase; Humans; Ligands; Metabolic Diseases; Natriuretic Peptides; Neprilysin; Phosphodiesterase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction

Natriuretic peptides are cardiac-derived hormones with a range of protective functions, including natriuresis, diuresis, vasodilation, lusitropy, lipolysis, weight loss, and improved insulin sensitivity. Their actions are mediated through membrane-bound guanylyl cyclases that lead to production of the intracellular second-messenger cyclic guanosine monophosphate. A growing body of evidence demonstrates that genetic and acquired deficiencies of the natriuretic peptide system can promote hypertension, cardiac hypertrophy, obesity, diabetes mellitus, the metabolic syndrome, and heart failure. Clinically, natriuretic peptides are robust diagnostic and prognostic markers, and augmenting natriuretic peptides is a target for therapeutic strategies in cardiometabolic disease. This review will summarize current understanding and highlight novel aspects of natriuretic peptide biology.

Topics: Biomarkers; Cardiovascular Diseases; Cyclic GMP; Humans; Metabolic Diseases; Natriuretic Peptides; Second Messenger Systems

Since the discovery of natriuretic peptides (NPs) by de Bold et al. in 1981, the cardiovascular community has been well aware that they exert potent effects on vessels, heart remodeling, kidney function, and the regulation of sodium and water balance. Who would have thought that NPs are also able to exert metabolic effects and contribute to an original cross talk between heart, adipose tissues, and skeletal muscle? The attention on the metabolic role of NPs was awakened in the year 2000 with the discovery that NPs exert potent lipolytic effects mediated by the NP receptor type A/cGMP pathway in human fat cells and that they contribute to lipid mobilization in vivo. In this review, we will discuss the biological effects of NPs on the main tissues involved in the regulation of energy metabolism (i.e., white and brown adipose tissues, skeletal muscle, liver, and pancreas). These recent results on NPs are opening a new chapter into the physiological properties and therapeutic usefulness of this family of hormones.

Topics: Adipokines; Adipose Tissue; Adipose Tissue, Brown; Animals; Cyclic GMP; Cytokines; Energy Metabolism; Homeostasis; Humans; Lipid Metabolism; Metabolic Diseases; Muscle, Skeletal; Natriuretic Peptides; Signal Transduction; Vascular Diseases

Numerous general metabolic systems are disturbed in association with psoriasis: the frequency of diabetes mellitus and of hyperuricaemia, lipid disturbances and a decrease in folates as a result of their excessive consumption by the skin. Cutaneous metabolism is also altered. Numerous compounds are formed in excess from glucose: amino acids, fatty acids and sterols, lactic acid--the formation of which persists in the corneal layer, ribose and ribulose--synthesised as a result of glucose-6-phosphate-dehydrogenase hyperactivity (role of the increased catabolism of dehydro-epi-androsterone) and uronic acids. The accumulation of glycogen is probably due to excessive synthesis and impaired breakdown. These abnormalities may exist to a lesser extent in healthy skin. In the corneal layer there are lipid vacuoles visible under the electron microscope. Lipogenesis is increased. The same may apply to lipolysis (blood NEFA are increased). Esterification of cholesterol is decreased. The utilisation of ATP by cell membranes is probably diminished (low ATP ase activity). The absence of formation of keratohyaline is due to persistence of the repression which normally prevents it in the mucus body. Renewal of collagen appears increased. The synthesis of DNA is increased in the lesions and neighbouring areas. It is possible that these various abnormalities are dependent upon modifications in the regulator systems of cyclic AMP and GMP, variations in which are however discussed.

Topics: Adenosine Triphosphatases; Blood Glucose; Collagen; Cyclic AMP; Cyclic GMP; DNA; Glycogen; Glycolysis; Humans; Keratins; Lipid Metabolism; Metabolic Diseases; Metals; Mitochondria; Oxygen Consumption; Pentosephosphates; Proteins; Psoriasis; Skin