cyclic-gmp and Acute-Coronary-Syndrome

Dipyridamole (DP) is a phosphodiesterase inhibitor that increases the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP) by preventing their conversion to AMP and GMP, respectively. By increasing cAMP and cGMP levels in platelets, DP reversibly inhibits platelet aggregation and platelet-mediated thrombotic disease. In addition, DP may potentiate some of the vascular protective effects of endothelium-derived nitric oxide (NO), which increases cGMP by stimulating soluble guanylyl cyclase. Endothelium-derived NO is an important regulator of vascular tone, blood flow, and tissue perfusion. Indeed, endothelial NO synthase-deficient (eNOS-/-) mice exhibit elevated systemic blood pressure and have larger myocardial and cerebral infarct size after ischemic injury. Other NO/cGMP-dependent effects that may be potentiated by DP include inhibition of vascular smooth muscle proliferation and prevention of endothelial-leukocyte interaction. In addition, DP increases local concentrations of adenosine and prostacyclin, which could affect vascular tone and inflammation. Finally, DP has antioxidant properties, which could stabilize platelet and vascular membranes as well as prevent the oxidation of low-density lipoprotein. These platelet and nonplatelet actions of DP may contribute to some of its therapeutic benefits in vascular disease.

Topics: Acute Coronary Syndrome; Animals; Cyclic AMP; Cyclic GMP; Dipyridamole; Disease Models, Animal; Endothelium, Vascular; Humans; Mice; Nitric Oxide; Oxidation-Reduction; Phosphodiesterase Inhibitors; Platelet Aggregation; Prognosis; Stroke; Survival Rate; Treatment Outcome

A multi-class classification model for acute coronary syndrome (ACS) remains to be constructed based on multi-fluid metabolomics. Major confounders may exert spurious effects on the relationship between metabolism and ACS. The study aims to identify an independent biomarker panel for the multiclassification of HC, UA, and AMI by integrating serum and urinary metabolomics. We performed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics study on 300 serum and urine samples from 44 patients with unstable angina (UA), 77 with acute myocardial infarction (AMI), and 29 healthy controls (HC). Multinomial machine learning approaches, including multinomial adaptive least absolute shrinkage and selection operator (LASSO) regression and random forest (RF), and assessment of the confounders were applied to integrate a multi-class classification biomarker panel for HC, UA and AMI. Different metabolic landscapes were portrayed during the transition from HC to UA and then to AMI. Glycerophospholipid metabolism and arginine biosynthesis were predominant during the progression from HC to UA and then to AMI. The multiclass metabolic diagnostic model (MDM) dependent on ACS, including 2-ketobutyric acid, LysoPC(18:2(9Z,12Z)), argininosuccinic acid, and cyclic GMP, demarcated HC, UA, and AMI, providing a C-index of 0.84 (HC vs. UA), 0.98 (HC vs. AMI), and 0.89 (UA vs. AMI). The diagnostic value of MDM largely derives from the contribution of 2-ketobutyric acid, and LysoPC(18:2(9Z,12Z)) in serum. Higher 2-ketobutyric acid and cyclic GMP levels were positively correlated with ACS risk and atherosclerosis plaque burden, while LysoPC(18:2(9Z,12Z)) and argininosuccinic acid showed the reverse relationship. An independent multiclass biomarker panel for HC, UA, and AMI was constructed using the multinomial machine learning methods based on serum and urinary metabolite signatures.

Topics: Acute Coronary Syndrome; Angina, Unstable; Argininosuccinic Acid; Biomarkers; Chromatography, Liquid; Cyclic GMP; Humans; Myocardial Infarction; Tandem Mass Spectrometry

This study was aimed at evaluating whether the nitric oxide (NO)/cyclic GMP (cGMP) signaling pathway is altered in platelets from patients with an acute coronary syndrome (unstable angina and acute myocardial infarction). We investigated 10 patients with unstable angina (UA), 14 with acute myocardial infarction (AMI) and 14 age and sex-matched healthy subjects. The serum markers of platelet activation (sP-selectin), inflammation (TNF-alpha and erythrocyte sedimentation rate), thrombotic state (fibrinogen) and plaque disruption were significantly higher in both UA and AMI patients compared to the healthy controls. In their platelets we assessed the cGMP levels in basal conditions and after stimulation with sodium nitroprusside (SNP), and performed Western blot analysis of homogenates to measure the expression of soluble guanylate cyclase isoforms. Basal levels of cGMP (pmol/10(10) platelets) were significantly higher in platelets from UA patients (1,097 +/- 111; p < 0.0001) and AMI (1,122 +/- 77; p < 0.0001) compared to those collected from healthy controls (497 +/- 80). The platelets of AMI patients exhibited a lack of cGMP increase after SNP stimulation in comparison with UA patients. The phosphorylation of upstream (Akt1 protein kinase alpha and endothelial NO synthase) and downstream (vasodilator-stimulated phosphoprotein, VASP) signaling proteins of the NO/cGMP pathway was investigated: serine phosphorylation in Akt1, eNOS and VASP was enhanced in platelets from UA and AMI patients when compared to controls. Furthermore, in AMI patients the inhibitors of guanylate cyclase and cGMP-dependent protein kinase did not revert the VASP phosphorylation. These data suggest that platelets from AMI patients are more resistant to SNP stimulation, not only as cGMP production, but also in terms of VASP activation. From these ex vivo results we hypothesize that the increased inflammatory state which often accompanies patients with cardiovascular diseases might promote a platelet preactivation resulting in their reduced sensitivity to NO.

Topics: Acute Coronary Syndrome; Aged; Blood Platelets; Case-Control Studies; Cyclic GMP; Female; Humans; Male; Middle Aged; Nitric Oxide; Signal Transduction