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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Jean-Luc Balligand ,
In the first lecture, Thomas Luescher illustrated the importance of p66shc as a gene contributing to the decrease in endothelial function with ageing, associated with decreased NO bioavailability despite increased eNOS expression. The paradox is explained by a PKCbeta2 and p66shc mediated mechanism that increases ROS production from mitochondria resulting in peroxinitrite production and dysregulation of endothelial targets. This mechanism operates not only with ageing but also in response to hyperglycaemia. Luescher’s team further demonstrated that this accounts for persistent endothelial dysfunction despite correction of hyperglycaemia, the so=called “hyperglycaemic memory” (this involves epigenetic regulation of p66shc, cf Young Investigator Award in Basic Science).The clinical relevance is reinforced from the observation that p66shc is upregulated in acute coronary syndromes. Prof. Luescher also illustrated the role of Jun D as a gene that, conversely, protects against ageing; accordingly, JunD deficient mice exhibit increased oxidant stress and endothelial dysfunction. This complex role of ROS produced from different cellular compartments may explain the failure of therapeutic strategies using non-specific antioxidants as anti-atherosclerotic medications.
Next, R Boeger from Hamburg reviewed the ample biochemical evidence for the inhibition of NOS (and the L arginine transporter CAT1) by ADMA at low concentrations such as measured in vivo in patients with cardiovascular risk factors. As a result ADMA is clearly proatherogenic by inhibiting NO production (in addition, perhaps to NOS uncoupling). Importantly, methylation of L-arginine is catalyzed by a methyltransferase the activity of which is promoted by vitamin B treatment, probably explaining the failure of vitamin B supplementation in clinical trials. ADMA is degraded by DDAH; genetic experiments using overexpressors and knockout mice established the key role of DDAH1 as the main isoform. Importantly, several studies established plasma ADMA as a predictor of mortality and GWAS association studies for ADMA clearly highlighted DDAH1 as a risk gene in human studies.
C Antoniades from Oxford then summarized the current knowledge on the mechanisms of NOS uncoupling, a major source of superoxide anions production and endothelial NO dependent dysfunction. He highlighted the importance of the bioavailability of reduced THB4 for the enzyme, as reflected by the measured ratio of BH4/BH2 in plasma (but more importantly in vessel endothelium). Accordingly, uncoupling can be reversed by endogenous supply of THB4 by GTPCH, a key enzyme for its production; among other pleiotropic effects, statins just do that by upregulating GTPCH and decreasing oxidation by inhibiting NOX-dependent superoxide production (this may involve Rac1 downregulation but also other mechanisms such as caveolin1 downregulation- cf Lobysheva et al ATVB 2011). This has spurred several efforts to develop pharmacologic strategies to restore BH4; folic acid has not fulfilled this promise in clinical trials, perhaps because of its ineffectiveness to replenish the vascular compartment. An alternative mechanism involves adiponectin (potentially produced from perivascular fat), that increases BH4 but also activates eNOS phosphorylation. The relevance of this mechanism in the clinic however remains to be established.
Finally, H Morawietz from Dresden highlighted the pleiotropic roles of NADPH isoforms in endothelial function/dysfunction. He emphasized the distinctive properties of NOX4 and NOX5 (in humans) as producers of H2O2 (as opposed to NOX1/2 that mainly produce superoxide anions), justifying their dual properties as deleterious or protective enzymes depending on the context. Conversely, vascular NOX2 appears to mediate detrimental effects, as illustrated from genetic experiments in ApoE-/-XNOX2+/- (that are protected from atherosclerosis compared with ApoEKO controls). Strikingly, NOX2 may also mediate endothelial damage by pollutant microparticles that would activate the enzyme through a TLR4-dependent pathway. Accordingly, the pharma industry has launched efforts to develop preferential NOX2 inhibitors for therapeutic use, but none has reached formal clinical trials yet. However, Morawietz illustrated the efficient downregulation of NADPH oxidase as part of the beneficial effects of statins and AT1 blockers (EPAS trial) as well as exercise training
From bench to practice: novel anti-atherogenic strategies to improve endothelial function
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