High-intensity interval training and moderate-intensity continuous training attenuate oxidative damage and promote myokine response in the skeletal muscle of ApoE KO mice on high-fat diet

The purpose of this study was to investigate the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the skeletal muscle in Apolipoprotein E knockout (ApoE KO) and wild-type (WT) C57BL/6J mice. ApoE KO mice fed with a high-fat diet were randomly allocated into: Control group without exercise (ApoE−/− CON), HIIT group (ApoE−/− HIIT), and MICT group (ApoE−/− MICT). Exercise endurance, blood lipid profile, muscle antioxidative capacity, and myokine production were measured after six weeks of interventions. ApoE−/− CON mice exhibited hyperlipidemia and increased oxidative stress, compared to the WT mice. HIIT and MICT reduced blood lipid levels, ROS production, and protein carbonyl content in the skeletal muscle, while it enhanced the GSH generation and potently promoted mRNA expression of genes involved in the production of irisin and BAIBA. Moreover, ApoE−/− HIIT mice had significantly lower plasma HDL-C content, mRNA expression of MyHC-IIx and Vegfa165 in EDL, and ROS level; but remarkably higher mRNA expression of Hadha in the skeletal muscle than those of ApoE−/− MICT mice. These results demonstrated that both exercise programs were effective for the ApoE KO mice by attenuating the oxidative damage and promoting the myokines response and production. In particular, HIIT was more beneficial to reduce the ROS level in the skeletal muscle

Exercice physique et athérosclérose (quels sont les mécanismes physiologiques et moléculaires de l exercice qui préviennent et protègent de l athérosclérose ?)

L athérosclérose, pathologie inflammatoire artérielle chronique, est à l origine de la plupart des maladies cardiovasculaires qui constituent l une des premières causes de morbidité et mortalité en France. Les études observationnelles et expérimentales montrent que l exercice physique prévient la mortalité cardiovasculaire. Cependant, les mécanismes précisant les bénéfices cliniques de l exercice sur l athérosclérose sont encore largement inconnus. Le but général de ce travail a donc été d explorer, en utilisant un modèle expérimental d athérosclérose, la souris hypercholestérolémique génétiquement dépourvue en apolipoprotéine E (apoE-/-), les mécanismes athéro-protecteurs de l exercice. La dysfonction endothéliale, généralement associée aux facteurs de risque cardiovasculaire, serait l une des étapes précoces majeures de l athérogenèse. Elle est caractérisée par une diminution de la biodisponibilité en monoxyde d azote (NO) avec la perte de ses propriétés vasculo-protectrices, ce qui favorise un climat pro-athérogène (stress oxydatif, adhésion et infiltration des cellules inflammatoires dans la paroi artérielle ) conduisant à la formation de la plaque athéromateuse. L objectif de notre premier travail a donc été d explorer les effets de l exercice d une part, sur le développement des plaques athéromateuses et d autre part, sur la fonction endothéliale de la souris apoE-/-. Nos résultats montrent que l exercice réduit significativement l extension de l athérosclérose et prévient la dysfonction endothéliale. L explication pharmacologique montre que l exercice stimule la fonction endothéliale via, notamment, une plus grande sensibilité des récepteurs endothéliaux muscariniques, ce qui active les événements signalétiques cellulaires récepteurs-dépendants à l origine d une bioactivité accrue de NO. Les complications cliniques graves de l athérosclérose sont induites par la rupture de la plaque instable provoquant la formation d un thrombus occlusif et l ischémie du territoire tissulaire en aval. L objectif de notre deuxième travail a été d examiner l effet de l exercice sur la qualité/stabilité de la plaque. Nos résultats indiquent que l exercice de longue durée stabilise la plaque en augmentant le nombre de cellules musculaires lisses et en diminuant le nombre de macrophages intra-plaques. Nos résultats montrent aussi que la phosphorylation de la eNOS (NO Synthase endothéliale) Akt-dépendante n est pas le mécanisme moléculaire majeur à l origine de ce bénéfice. Enfin, dans notre troisième travail, nous avons investigué l effet de l exercice sur le développement de la plaque vulnérable. Nos résultats montrent, chez un modèle murin de plaque instable (modèle d hypertension rénovasculaire à rénine et angiotensine II élevés) que l exercice prévient l apparition de la plaque vulnérable indépendamment d un effet hémodynamique. Ce bénéfice serait associé à une diminution de l expression vasculaire des récepteurs AT1 de l Angiotensine II. Nos résultats justifient l importance de l exercice comme outil préventif des maladies cardiovasculaires.Atherosclerosis, a chronic inflammatory disease, is one of the main causes of morbidity and mortality in France. Observational and experimental data indicate that regular physical exercise has a positive impact on cardiovascular mortality. However, the mechanisms by which exercise exerts clinical benefits on atherosclerosis are still unknown. The general aim of this work was to elucidate the anti-atherosclerotic effects of exercise, using a mouse model of atherosclerosis: the apolipoprotein E-deficient mice (apoE-/- mice). Endothelial dysfunction, generally associated with cardiovascular risk factors, has been recognized to be a major and early step in atherogenesis. Endothelial dysfunction is characterized by Nitric Oxide (NO) biodisponibility reduction with loss of NO-mediated vasculoprotective actions. This leads to vascular effects such as increased oxidative stress and increased adhesion of inflammatory cells into arterial wall thus playing a role in atherosclerotic plaque development. Therefore, one of the objective of our study was to explore the effects of exercise on atherosclerotic plaque extension and on endothelial function in apoE-/- mice. Results show that exercise significantly reduces plaque progression and prevents endothelial dysfunction. Pharmacological explanation indicates that exercise stimulates endothelial function by increasing muscarinic receptors sensitivity which in turn activates intracellular signalling receptor-dependent events leading to increased NO bioactivity. The clinical manifestations of atherosclerosis are the consequences of unstable plaque rupture with thrombus formation leading to tissue ischemia. The second aim of our work was to determine the effect of exercise on plaque stability. We demonstrate that long-term exercise stabilizes atherosclerotic plaques as shown by decreased macrophage and increased Smooth Muscle Cells plaque content. Our results also suggest that the Akt-dependent eNOS phosphorylation pathway is not the primary molecular mechanism mediating these beneficial effects. Finally, we assessed a putative beneficial effect of exercise on vulnerable plaque development. In a mouse model of Angiotensine II (Ang II)-mediated vulnerable atherosclerotic plaques, we provide fist evidence that exercise prevents atherosclerosis progression and plaque vulnerability. The beneficial effect of swimming was associated with decreased aortic Ang II AT1 receptor expression independently from any hemodynamic change. These findings suggest clinical benefit of exercise in terms of cardiovascular event protection.BESANCON-BU Médecine pharmacie (250562102) / SudocSudocFranceF

The Role of Neutrophils in Lower Limb Peripheral Artery Disease: State of the Art and Future Perspectives

In recent years, increasing attention has been paid to the role of neutrophils in cardiovascular (CV) disease (CVD) with evidence supporting their role in the initiation, progression, and rupture of atherosclerotic plaque. Although these cells have long been considered as terminally differentiated cells with a relatively limited spectrum of action, recent research has revealed intriguing novel cellular functions, including neutrophil extracellular trap (NET) generation and inflammasome activation, which have been linked to several human diseases, including CVD. While most research to date has focused on the role of neutrophils in coronary artery and cerebrovascular diseases, much less information is available on lower limb peripheral artery disease (PAD). PAD is a widespread condition associated with great morbidity and mortality, though physician and patient awareness of the disease remains low. To date, several studies have produced some evidence on the role of certain biomarkers of neutrophil activation in this clinical setting. However, the etiopathogenetic role of neutrophils, and in particular of some of the newly discovered mechanisms, has yet to be fully elucidated. In the future, complementary assessment of neutrophil activity should improve CV risk stratification and provide personalized treatments to patients with PAD. This review aims to summarize the basic principles and recent advances in the understanding of neutrophil biology, current knowledge about the role of neutrophils in atherosclerosis, as well as available evidence on their role of PAD

Primers for quantitative real-time RT-PCR.

<p>Primers for quantitative real-time RT-PCR.</p

Comparison of atherosclerotic plaque extension among 8-week 2K1C ApoE^-/-SED and EXE mice.

<p>A, Representative photomicrographs of en face aortas stained with Oil red O. B, Quantitative morphometric analysis of Oild red O-stained lesions as percentage of total aorta surface. N = 7 mice per group. Box plots display interquartile ranges, whiskers indicate minimum and maximum values.</p

Comparison of local and systemic cytokines expression among 8-week 2K1C ApoE^-/- SED and EXE mice.

<p>Aortic (A) and splenic (B) mRNA expression of pro-inflammatory cytokines IL-1β, IL-18, TNF-α and IL-6 cytokines and anti-inflammatory cytokines IL-1ra, IL-4 and/or IL-10 measured by quantitative real-time PCR. N = 6 mice in SED group; N = 7 mice in EXE group. Data are expressed as fold change ± SD compared to SED (set at 1) after normalization to the 36B4 housekeeping gene.</p

Comparison of local and systemic CD4⁺ T helper cells and macrophage polarization markers expression among 8-week 2K1C ApoE^-/- SED and EXE mice.

<p>Aortic (A) and splenic (B) mRNA expression of pro-inflammatory M1 macrophages (iNOS) and Th1 cells (T-bet) and anti-inflammatory M2 macrophages (Arg1) and Th2 cells (GATA3) measured by quantitative real-time PCR. Fold change ratios of iNOS to Arg1 (M1/M2 balance marker) and of T-bet to GATA3 (Th1/Th2 cells balance marker) were calculated. N = 6 mice in SED group; N = 7 mice in EXE group. Data are expressed as fold change ± SD compared to SED (set at 1) after normalization to the 36B4 housekeeping gene.</p

Comparison of local endothelial adhesion molecules expression among 8-week 2K1C ApoE^-/- SED and EXE mice.

<p>Aortic mRNA expression of VCAM-1 (A) and ICAM-1 (B) measured by quantitative real-time RT-PCR. Data are expressed as fold change ± SD compared to SED (set at 1) after normalization to the 36B4 housekeeping gene.</p

Comparison of physiological parameters in 8-week 2K1C ApoE^-/- SED and EXE mice.

<p>MBP: mean blood pressure; HR: heart rate; PRA: plasma renin activity.</p><p>*P<0.05 versus SED.</p><p>N = 13–14 mice per group for MBP, HR and PRA, and N = 6 mice per group for total cholesterol levels.</p><p>Data are presented as mean ± SD.</p><p>Comparison of physiological parameters in 8-week 2K1C ApoE^-/- SED and EXE mice.</p