Redox biomarkers in cardiovascularmedicine

The central role of oxidative signalling in cardiovascular pathophysiology positions biometric measures of redox state as excellent markers for research and clinical application. However, despite this tantalizing biological plausibility, no redox biomarker is currently in widespread clinical use. Major recent insights into the mechanistic complexities of redox signalling may yet provide the opportunity to identify markers that most closely reflect the underlying pathobiology. Such redox biomarkers may, in principle, quantify the integrated effects of various known and unknown pathophysiological drivers of cardiovascular disease processes. Recent advances with the greatest potential include assays measuring post-translational oxidative modifications that have significant cellular effects. However, analytical issues, including the relative instability of redox-modified products, remain a major technical obstacle. Appreciation of these challenges may facilitate future development of user-friendly markers with prognostic value in addition to traditional risk factors, and which could be used to guide personalized cardiovascular therapies. We review both established and recently identified biomarkers of redox signalling, and provide a realistic discussion of the many challenges that remain if they are to be incorporated into clinical practice. Despite the current lack of redox biomarkers in clinical application, the integral role of reactive oxygen species in pathogenesis of cardiovascular disease provides a strong incentive for continued efforts.Keyvan Karimi Galougahi, Charalambos Antoniades, Stephen J. Nicholls, Keith M. Channon and Gemma A. Figtre

β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia.

BACKGROUND: Perturbed balance between NO and O2 (•-). (ie, NO/redox imbalance) is central in the pathobiology of diabetes-induced vascular dysfunction. We examined whether stimulation of β3 adrenergic receptors (β3 ARs), coupled to endothelial nitric oxide synthase (eNOS) activation, would re-establish NO/redox balance, relieve oxidative inhibition of the membrane proteins eNOS and Na(+)-K(+) (NK) pump, and improve vascular function in a new animal model of hyperglycemia. METHODS AND RESULTS: We established hyperglycemia in male White New Zealand rabbits by infusion of S961, a competitive high-affinity peptide inhibitor of the insulin receptor. Hyperglycemia impaired endothelium-dependent vasorelaxation by "uncoupling" of eNOS via glutathionylation (eNOS-GSS) that was dependent on NADPH oxidase activity. Accordingly, NO levels were lower while O2 (•-) levels were higher in hyperglycemic rabbits. Infusion of the β3 AR agonist CL316243 (CL) decreased eNOS-GSS, reduced O2 (•-), restored NO levels, and improved endothelium-dependent relaxation. CL decreased hyperglycemia-induced NADPH oxidase activation as suggested by co-immunoprecipitation experiments, and it increased eNOS co-immunoprecipitation with glutaredoxin-1, which may reflect promotion of eNOS de-glutathionylation by CL. Moreover, CL reversed hyperglycemia-induced glutathionylation of the β1 NK pump subunit that causes NK pump inhibition, and improved K(+)-induced vasorelaxation that reflects enhancement in NK pump activity. Lastly, eNOS-GSS was higher in vessels of diabetic patients and was reduced by CL, suggesting potential significance of the experimental findings in human diabetes. CONCLUSIONS: β3 AR activation restored NO/redox balance and improved endothelial function in hyperglycemia. β3 AR agonists may confer protection against diabetes-induced vascular dysfunction

Targeting Cardiac Myocyte Na⁺-K⁺ Pump Function With β3 Adrenergic Agonist in Rabbit Model of Severe Congestive Heart Failure.

BackgroundAbnormally high cytosolic Na+ concentrations in advanced heart failure impair myocardial contractility. Stimulation of the membrane Na+-K+ pump should lower Na+ concentrations, and the β3 adrenoceptor (β3 AR) mediates pump stimulation in myocytes. We examined if β3 AR-selective agonists given in vivo increase myocyte Na+-K+ pump activity and reverse organ congestion in severe heart failure (HF).MethodsIndices for HF were lung-, heart-, and liver: body weight ratios and ascites after circumflex coronary artery ligation in rabbits. Na+-K+ pump current, Ip, was measured in voltage-clamped myocytes from noninfarct myocardium. Rabbits were treated with the β3 AR agonists CL316,243 or ASP9531, starting 2 weeks after coronary ligation.ResultsCoronary ligation caused ascites in most rabbits, significantly increased lung-, heart-, and liver: body weight ratios, and decreased Ip relative to that for 10 sham-operated rabbits. Treatment with CL316,243 for 3 days significantly reduced lung-, heart-, and liver: body weight ratios and prevalence of ascites in 8 rabbits with HF relative to indices for 13 untreated rabbits with HF. It also increased Ip significantly to levels of myocytes from sham-operated rabbits. Treatment with ASP9531 for 14 days significantly reduced indices of organ congestion in 6 rabbits with HF relative to indices of 6 untreated rabbits, and it eliminated ascites. β3 AR agonists did not significantly change heart rates or blood pressures.ConclusionsParallel β3 AR agonists-induced reversal of Na+-K+ pump inhibition and indices of congestion suggest pump inhibition is a useful target for treatment with β3 AR agonists in congestive HF

Apolipoprotein A-I Reduces In-Stent Restenosis and Platelet Activation and Alters Neointimal Cellular Phenotype

Summary: Even the most advanced drug-eluting stents evoke unresolved issues, including chronic inflammation, late thrombosis, and neoatherosclerosis. This highlights the need for novel strategies that improve stent biocompatibility. Our studies show that apolipoprotein A-I (apoA-I) reduces in-stent restenosis and platelet activation, and enhances endothelialization. These findings have therapeutic implications for improving stent biocompatibility. Key Words: apolipoprotein A-I, endothelialization, neointimal hyperplasia, platelet activation, stent biocompatibilit