Nitric oxide & cardiovascular disease.pdf

drsinatra.com Nitric oxide & cardiovascular disease DR SA R A H T R I NDER S.T RINDER@SURR EY. AC.U K 3 0 AY04 Outline Risk factors for reduced NO and cardiovascular disease (CVD). Endothelial dysfunction and NO. How is NO protective against CVD? How can we i...

drsinatra.com Nitric oxide & cardiovascular disease DR SA R A H T R I NDER S.T RINDER@SURR EY. AC.U K 3 0 AY04 Outline Risk factors for reduced NO and cardiovascular disease (CVD). Endothelial dysfunction and NO. How is NO protective against CVD? How can we increase NO signalling as a possible therapeutic? Lundberg et al., 2015 Lundberg et al., 2015 NO reacts – diverse signalling! NO NO3- NOS NO2- Transition Other radicals Oxidation metals sGC CCO RNS NO inactivation Mitochondrial O2- scavenging Altered protein cGMP signalling function function NO resistance? Basal redox state – key Determines responsiveness of sGC NOS uncoupling Inflammation ↑arginase 2 catabolises L-arginine ↑ ROS NO - CV protection Vasodilatation – sGC-cGMP pathway Anti-platelet aggregation and adhesion Inhibits monocytes adhesion and migration Inhibits SMC & fibroblast proliferation NO - cardioprotective Control of heart rate & contractility Exerts positive inotropic effects cGMP Ryanodine receptor Protective in cardiac ischaemia Mechanism unclear Mitochondria important? NO – cardioprotective - mitochondria Lundberg et al., 2015 Lecture 2 - How increase NO/cGMP signalling? Lundberg et al., 2015 Generate NO Inhaled NO – persistent pulmonary hypertension in newborns (PPHN) Enhance NO synthesis L-arginine – direct delivery/arginase inhibition BH4 – supplementation Inhibit endogenous NOS inhibitors Current therapies activate eNOS Statins Corticosteroids 2nd gen β blockers Prevent NO breakdown ACE inhibitors NOX inhibitors Lundberg et al., 2015  Stimulate down stream pathways ANP ANP NEPi (Ecadotril) NEP Endothelium NO PDE2i (BAY60-5770) NPR-A Fe PDE5i (Sildenafil) pGC sGC GTP cGMP GTP PDE2/5 GMP Bubb & Trinder et al., 2014 Smooth muscle cell VASODILATATION sGC activators & stimulators (Stasch et al. 2011) Polyphenols & NO Lundberg et al., 2015 What diseases targets? Learning objectives Discuss the risk factors for reduced NO and cardiovascular disease (CVD). Discuss the role of endothelial dysfunction and NO in CVD. Explain how is NO protective against CVD. Discuss how NO signalling can be increased to manipulate it’s therapeutic potential in CVD? Papers LUNDBERG, J. O., GLADWIN, M. T. & WEITZBERG, E. 2015. Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov, 14, 623-641. STASCH, J.-P., PACHER, P. & EVGENOV, O. V. 2011. Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease. Circulation, 123, 2263-2273. BUBB, K. J., TRINDER, S. L., BALIGA, R. S., PATEL, J., CLAPP, L. H., MACALLISTER, R. J. & HOBBS, A. J. 2014. Inhibition of Phosphodiesterase 2 Augments cGMP and cAMP Signaling to Ameliorate Pulmonary Hypertension. Circulation.