A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Postoperative atrial fibrillation:mechanisms, manifestations and management

Postoperative atrial fibrillation (POAF) complicates 20-40% of cardiac surgical procedures and 10-20% of non-cardiac thoracic operations. Typical features include onset at 2-4 days postoperatively, episodes that are often fleeting and a self-limited time course. Associated adverse consequences of POAF include haemodynamic instability, increased risk of stroke, lengthened hospital and intensive care unit stays and greater costs. Underlying mechanisms are incompletely defined but include intraoperative and postoperative phenomena, such as inflammation, sympathetic activation and cardiac ischaemia, that combine to trigger atrial fibrillation, often in the presence of pre-existing factors, making the atria vulnerable to atrial fibrillation induction and maintenance. A better understanding of the underlying mechanisms might enable the identification of new therapeutic targets. POAF can be prevented by targeting autonomic alterations and inflammation. beta-Blocker prophylaxis is the best-established preventive therapy and should be started or continued before cardiac surgery, unless contraindicated. When POAF occurs, rate control usually suffices, and routine rhythm control is unnecessary; rhythm control should be reserved for patients who develop haemodynamic instability or show other indications that rate control alone will be insufficient. In this Review, we summarize the epidemiological and clinical features of POAF, the available pathophysiological evidence from clinical and experimental investigations, the results of prophylactic and therapeutic approaches and the consensus recommendations of various national and international societies