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      Physical Exercise Protects Against Endothelial Dysfunction in Cardiovascular and Metabolic Diseases

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          Abstract

          Increasing evidence shows that endothelial cells play critical roles in maintaining vascular homeostasis, regulating vascular tone, inhibiting inflammatory response, suppressing lipid leakage, and preventing thrombosis. The damage or injury of endothelial cells induced by physical, chemical, and biological risk factors is a leading contributor to the development of mortal cardiovascular and cerebrovascular diseases. However, the underlying mechanism of endothelial injury remains to be elucidated. Notably, no drugs effectively targeting and mending injured vascular endothelial cells have been approved for clinical practice. There is an urgent need to understand pathways important for repairing injured vasculature that can be targeted with novel therapies. Exercise training-induced protection to endothelial injury has been well documented in clinical trials, and the underlying mechanism has been explored in animal models. This review mainly summarizes the protective effects of exercise on vascular endothelium and the recently identified potential therapeutic targets for endothelial dysfunction.

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          Most cited references125

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          Lack of exercise is a major cause of chronic diseases.

          Chronic diseases are major killers in the modern era. Physical inactivity is a primary cause of most chronic diseases. The initial third of the article considers: activity and prevention definitions; historical evidence showing physical inactivity is detrimental to health and normal organ functional capacities; cause versus treatment; physical activity and inactivity mechanisms differ; gene-environment interaction (including aerobic training adaptations, personalized medicine, and co-twin physical activity); and specificity of adaptations to type of training. Next, physical activity/exercise is examined as primary prevention against 35 chronic conditions [accelerated biological aging/premature death, low cardiorespiratory fitness (VO2max), sarcopenia, metabolic syndrome, obesity, insulin resistance, prediabetes, type 2 diabetes, nonalcoholic fatty liver disease, coronary heart disease, peripheral artery disease, hypertension, stroke, congestive heart failure, endothelial dysfunction, arterial dyslipidemia, hemostasis, deep vein thrombosis, cognitive dysfunction, depression and anxiety, osteoporosis, osteoarthritis, balance, bone fracture/falls, rheumatoid arthritis, colon cancer, breast cancer, endometrial cancer, gestational diabetes, pre-eclampsia, polycystic ovary syndrome, erectile dysfunction, pain, diverticulitis, constipation, and gallbladder diseases]. The article ends with consideration of deterioration of risk factors in longer-term sedentary groups; clinical consequences of inactive childhood/adolescence; and public policy. In summary, the body rapidly maladapts to insufficient physical activity, and if continued, results in substantial decreases in both total and quality years of life. Taken together, conclusive evidence exists that physical inactivity is one important cause of most chronic diseases. In addition, physical activity primarily prevents, or delays, chronic diseases, implying that chronic disease need not be an inevitable outcome during life. © 2012 American Physiological Society. Compr Physiol 2:1143-1211, 2012.
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            Small vessel disease: mechanisms and clinical implications

            Small vessel disease is a disorder of cerebral microvessels that causes white matter hyperintensities and several other common abnormalities (eg, recent small subcortical infarcts and lacunes) seen on brain imaging. Despite being a common cause of stroke and vascular dementia, the underlying pathogenesis is poorly understood. Research in humans has identified several manifestations of cerebral microvessel endothelial dysfunction including blood-brain barrier dysfunction, impaired vasodilation, vessel stiffening, dysfunctional blood flow and interstitial fluid drainage, white matter rarefaction, ischaemia, inflammation, myelin damage, and secondary neurodegeneration. These brain abnormalities are more dynamic and widespread than previously thought. Relationships between lesions and symptoms are highly variable but poorly understood. Major challenges are the determination of which vascular dysfunctions are most important in pathogenesis, which abnormalities are reversible, and why lesion progression and symptomatology are so variable. This knowledge will help to identify potential targets for intervention and improve risk prediction for individuals with small vessel disease.
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              AMPK and PPARdelta agonists are exercise mimetics.

              The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.
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                Author and article information

                Contributors
                junjiexiao@shu.edu.cn
                Journal
                J Cardiovasc Transl Res
                J Cardiovasc Transl Res
                Journal of Cardiovascular Translational Research
                Springer US (New York )
                1937-5387
                1937-5395
                17 September 2021
                : 1-17
                Affiliations
                [1 ]GRID grid.39436.3b, ISNI 0000 0001 2323 5732, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, , Shanghai University, ; Nantong, 226011 China
                [2 ]GRID grid.39436.3b, ISNI 0000 0001 2323 5732, Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, , Shanghai University, ; 333 Nan Chen Road, Shanghai, 200444 China
                [3 ]GRID grid.38142.3c, ISNI 000000041936754X, Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, ; Boston, MA 02114 USA
                Author notes

                Editor-in-Chief Enrique Lara-Pezzi oversaw the review of this article

                Author information
                http://orcid.org/0000-0002-9202-0003
                Article
                10171
                10.1007/s12265-021-10171-3
                8447895
                34533746
                e7fea0cf-6b60-4a26-ad76-fe0cacdaace6
                © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 15 July 2021
                : 2 September 2021
                Categories
                Review

                Cardiovascular Medicine
                vascular disease,endothelium dysfunction,exercise,therapeutic targets
                Cardiovascular Medicine
                vascular disease, endothelium dysfunction, exercise, therapeutic targets

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