Since the discovery in the 1980s that nitric oxide (NO) is in fact the elusive endothelium-derived relaxing factor, it has become evident that NO is not only a major cardiovascular signalling molecule, but that changes in its bioavailability are crucial in determining whether atherosclerosis will develop or not. Sustained high levels of harmful circulating stimuli associated with cardiovascular risk factors such as diabetes mellitus elicit responses in endothelial cells that appear sequentially, namely endothelial cell activation and endothelial dysfunction (ED).ED, characterised by reduced NO bioavailability, is now recognised by many as an early, reversible precursor of atherosclerosis. The pathogenesis of ED is multifactorial; however, oxidative stress appears to be the common underlying cellular mechanism in the ensuing loss of vaso-active, inflammatory, haemostatic and redox homeostasis in the body’s vascular system. The role of ED as a pathophysiological link between early endothelial cell changes associated with cardiovascular risk factors and the development of ischaemic heart disease is of importance to basic scientists and clinicians alike.

We assessed the myocardial susceptibility to ischemic-reperfusion injury in obese rat hearts in the absence and the presence of predicted circulating concentrations of insulin and fatty acids. Feeding rats a high-calorie diet resulted in increases in body weight, visceral fat content, cardiac hypertrophy, plasma insulin, nonesterified free fatty acid, and triglyceride concentrations. In the absence of both insulin and fatty acids in the coronary perfusate, the hearts of obese rats developed an increased infarct size (41.9 +/- 1.9% for obese vs. 22.9 +/- 2.3% for control, P < 0.05) and a reduced percent recovery of aortic output (4.2 +/- 4.2% for obese vs. 27.7 +/- 3.4% for controls, P < 0.05) after coronary artery occlusion and reperfusion. In the presence of insulin in the coronary perfusate, a cardioprotective effect was noted in both groups, an action that was greater in hearts from obese compared with control rats and which abolished the obesity-induced changes in infarct size (13.8 +/- 1.2% for controls vs. 21.0 +/- 1.6% for obese), and percent recovery of aortic output (60.2 +/- 4.7% for controls vs. 45.7 +/- 9.4% for obese). Fatty acids (0.7 mM, control; and 1.5 mM, obese) added to the coronary perfusate with in vivo concentrations of insulin dramatically increased infarct size (48.2 +/- 3.1% for obese, and 37.5 +/- 2.7% for control; P < 0.05 vs. without fatty acids) and decreased percent aortic output recovery (control, 10.4 +/- 5.2%, and obese 7.8 +/- 3.5%; P < 0.05 vs. without fatty acids) in both groups to similar values. In conclusion, in obesity, the impact of an increased susceptibility of the myocardium to ischemic-reperfusion injury on myocardial injury is likely to be overshadowed by the comparatively greater roles played by predicted increases in circulating insulin and fatty acids found in vivo. These data support the notion that adiposity per se is unlikely to be a valuable predictor of outcomes in ischemic-reperfusion injury.

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Mounting evidence points to increased rates of cardiovascular disease (CVD) among people living with HIV/AIDS (PLWHA). Endothelial dysfunction (loss of endothelium-dependent vascular relaxation in response to provasodilatory stimuli) constitutes an early pathophysiological event in atherogenesis and CVD. Both HIV-1 infection and antiretroviral therapy (ART) are implicated in the development of endothelial dysfunction; however, conclusions are frequently drawn from associations shown in epidemiological studies. In this narrative review of mainly in vitro and animal studies, we report on the current understanding of how various HIV-1 proteins, HIV-1-induced proinflammatory cytokines and common antiretroviral drugs directly impact vascular endothelial cells. Proposed cellular mechanisms underlying the switch to a dysfunctional state are discussed, including oxidative stress, impaired expression and regulation of endothelial nitric oxide (NO) synthase (eNOS) and increased expression of vascular adhesion molecules. From the literature, it appears that increased reactive oxygen species (ROS) production, linked to decreased NO bioavailability and ensuing endothelial dysfunction, may be proposed as a putative final common pathway afflicting the vascular endothelium in PLWHA. The HIV-1-proteins Tat, Gp120 and Nef in particular, the proinflammatory cytokine, TNF-α, and the antiretroviral drugs Efavirenz and Lopinavir, most commonly postulated to be primary causal agents of endothelial dysfunction, are also discussed. We conclude that, despite existing evidence from basic research papers, a significant gap remains in terms of the exact underlying cellular mechanisms involved in HIV-1 and ART induced endothelial dysfunction. Bridging this gap could help pave the way for future strategies to prevent and treat early cardiovascular changes in PLWHA.