The role of high density lipoprotein in the determination of the vascular effects of chronic exercise training in hypertensive patients

The original research article of Pagonas et al. entitled ‘The impact of aerobic and isometric exercise on different measures of dysfunctional high density lipoprotein in patients with hypertension’ investigated the differential effects of aerobic and resistance exercise training on the functional properties of high density lipoprotein (HDL) as potential mediators of the accompanied improvement of vascular function in hypertensive patients.1 Specifically, only chronic aerobic exercise downregulated circulating oxidized HDL (oxHDL) and the exercise-induced decrease in oxHDL correlated with the reduction of systolic, as well as diastolic, daytime ambulatory blood pressure (BP). No previous study has evaluated the role of HDL in the context of chronic exercise-induced amelioration of vascular function. The majority of studies investigating the impact of chronic exercise on serum lipoprotein levels revealed an upregulation of HDL-cholesterol (HDL-C), though this effect may be attenuated when exercise training is added on the top of statin therapy.2,3 However, convincing evidence derived from genetic studies raises the possibility that functionality of HDL appears to have a more important role to inhibit the process of atherosclerosis than the serum levels of HDL-C.4 In this respect, the evaluation of the role of HDL in the context of the beneficial cardiovascular effects of chronic exercise should be performed in terms of HDL functionality, rather than HDL-C levels. Apart from the well-known major role of HDL in reverse cholesterol transport, by which excess cholesterol is removed from peripheral vessels and then transferred to the liver for disposal, HDL exerts several other beneficial effects, including antioxidative, anti-inflammatory, endothelial/vasodilatory, antithrombotic and cytoprotective functions. Notably, Pagonas et al. demonstrated that aerobic exercise training at moderate intensity performed 30 min per day and 3–5 times per week for 12 weeks reduced circulating oxHDL, as a result of the exercise-induced antioxidative process. This finding is consistent with the previously reported decreased burden of oxidative stress in individuals who engage in chronic exercise.5,6 Taking into account that oxHDL has been shown to be characterized by impaired ability to promote cholesterol efflux from macrophage-derived foam cells, the above-mentioned reduction of circulating oxHDL after chronic exercise is expected to be accompanied by improved functional properties of HDL to decelerate the atherosclerotic process.7 Importantly, Pagonas et al. found that circulating oxHDL decreased without change in HDL-C, implying that the improvement of the functional properties of HDL may precede the well-known upregulation of HDL-C after chronic exercise.2 However, there was no change in the plasma levels of the complex haptoglobin-HDL, which is considered a dysfunctional HDL particle with decreased anti-inflammatory properties. Therefore, the beneficial effects of chronic aerobic exercise regarding HDL functionality appear to already emerge after 12 weeks of intervention, implying that aerobic exercise training may have a relevant role in the plaque stabilization during the early management of patients after an acute coronary syndrome. The endothelial/vasodilatory effects of HDL have been found to involve the stimulation of endothelial nitric oxide synthase (eNOS) via scavenger receptor-BI.8,9 Phosphorylation of eNOS at Ser-1177 is pivotal for nitric oxide generation, while phosphorylation of Thr-495 downregulates NO-production.8 The eNOS protein resides within a signalling module in caveolae of endothelial cells. Oxidized low-density lipoprotein (oxLDL) has been reported to cause depletion of caveolae from eNOS accompanied by attenuation of the acetylcholine-induced activation of eNOS, while HDL has been shown to reverse the oxLDL-induced impairment of endothelium-dependent vasorelaxation.9 However, oxHDL has been demonstrated to have no effect on the oxLDL-induced inhibition of endothelium-dependent vasorelaxation, implying that the vasorelaxant properties of HDL can be attributed the non-oxidized form of HDL.9 With regard to the influence of exercise on the HDL-induced vasodilation, Chen et al. reported an augmentation of the suppressive effect of HDL on the oxLDL-induced inhibition of endothelium-dependent vasodilation in thoracic aortas isolated from rats subjected to aerobic exercise training for eight weeks compared with aortas from sedentary rats.10 In this study, the effects of chronic exercise and HDL on the amelioration of vascular function, through the attenuation of oxLDL-induced inhibition of endothelium-dependent vasodilation, were reported to be independent and additive.10 Furthermore, Adams et al. demonstrated that HDL isolated from patients with heart failure subjected to 12-week aerobic exercise training was less oxidatively modified compared with baseline, while incubation of endothelial cells with this less oxidized HDL induced upregulation of Ser-1177 and downregulation of Thr-495 phosphorylations of eNOS, resulting in greater NO production.8 Therefore, aerobic exercise training appears to potentiate the vasorelaxant effects of HDL first through downregulation of dysfunctional oxHDL and second via enhanced responsiveness of endothelium to HDL (Figure 1). The proposed role of HDL in the mediation of the hypotensive effects of chronic aerobic exercise. BP: blood pressure; eNOS: endothelial nitric oxide synthase; HDL: high-density lipoprotein; NO: nitric oxide; oxLDL: oxidized low-density lipoprotein; ↑: increase; ↓: decrease; X: inhibition. Taking into account the above-mentioned considerations, the association reported by Pagonas et al.1 between the reduction of daytime ambulatory BP and decrease in circulating oxHDL after aerobic exercise training could be explained on the basis of the post-exercise elevation of serum non-oxidized HDL levels, which is characterized by a vasorelaxant potential (Figure 1). The fact that this association referred only to daytime and not to nighttime BP is in line with the previously shown preferential reduction of daytime BP after aerobic exercise training.11 Furthermore, the relationship reported by Pagonas et al. of the exercise-induced hypotensive effect with the chronically regulated oxHDL suggests that the underlying mechanisms of the hypotensive effect of exercise training may involve chronic exercise-induced vascular adaptations and are possibly not limited to an acute hypotensive effect of the preceding session of exercise. Chronic aerobic exercise has been found to induce both downregulation of markers of oxidative stress and upregulation of antioxidative defences, as well as elevation of serum HDL-C levels.2,5 These effects appear to be qualitatively similar with the ones induced by chronic resistance exercise.2,6 Circulating oxHDL after chronic exercise can be assumed to be the net result of two combined processes: the elevation of circulating HDL particles along with antioxidative modification of HDL particles (Figure 1). The report by Pagonas et al. of decrease in circulating oxHDL only after aerobic, but not following resistance exercise training, indicates that the latter process possibly prevails in individuals engaged in aerobic exercise training, while the two processes may occur in a more balanced manner in the case of chronic resistance exercise. This downregulation of circulating oxHDL only after aerobic exercise training is consistent with the previously reported greater post-exercise hypotension after aerobic exercise compared with resistance exercise.12 The clinical meaningfulness of the association reported by Pagonas et al. between oxHDL and BP after chronic exercise is possibly the emergence of oxHDL as a novel therapeutic target in hypertension. Specifically, apart from exercise training, other interventions leading to reduction of circulating oxHDL may prove promising additions to the existing armamentarium for the treatment of hypertension. Candidates of such therapies include interventions with known antioxidative potential, such as beetroot juice. In this case, the assessment of on-treatment circulating oxHDL during the development of such therapies may be a useful preclinical marker of the antihypertensive efficiency of these therapies. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.