title: Shear stress-induced mitochondrial biogenesis decreases the release of microparticles from endothelial cells.
abstract: The concept of enhancing structural integrity of mitochondria has emerged as a novel therapeutic option for cardiovascular disease. Flow-induced increase in laminar shear stress is a potent physiological stimulant associated with exercise, which exerts atheroprotective effects in the vasculature. However, the effect of laminar shear stress on mitochondrial remodeling within the vascular endothelium and its related functional consequences remain largely unknown. Using in vitro and in vivo complementary studies, here, we report that aerobic exercise alleviates the release of endothelial microparticles in prehypertensive individuals and that these salutary effects are, in part, mediated by shear stress-induced mitochondrial biogenesis. Circulating levels of total (CD31(+)/CD42a(-)) and activated (CD62E(+)) microparticles released by endothelial cells were significantly decreased (∼40% for both) after a 6-mo supervised aerobic exercise training program in individuals with prehypertension. In cultured human endothelial cells, laminar shear stress reduced the release of endothelial microparticles, which was accompanied by an increase in mitochondrial biogenesis through a sirtuin 1 (SIRT1)-dependent mechanism. Resveratrol, a SIRT1 activator, treatment showed similar effects. SIRT1 knockdown using small-interfering RNA completely abolished the protective effect of shear stress. Disruption of mitochondrial integrity by either antimycin A or peroxisome proliferator-activated receptor-γ coactivator-1α small-interfering RNA significantly increased the number of total, and activated, released endothelial microparticles, and shear stress restored these back to basal levels. Collectively, these data demonstrate a critical role of endothelial mitochondrial integrity in preserving endothelial homeostasis. Moreover, prolonged laminar shear stress, which is systemically elevated during aerobic exercise in the vessel wall, mitigates endothelial dysfunction by promoting mitochondrial biogenesis.
authors.affiliation: Department of Kinesiology, Temple University, Philadelphia, Pennsylvania;
authors.forename: Ji-Seok
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Kinesiology, Temple University, Philadelphia, Pennsylvania; Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Boa
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Kinesiology, Temple University, Philadelphia, Pennsylvania;
authors.forename: Hojun
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Kinesiology, Temple University, Philadelphia, Pennsylvania;
authors.forename: Sunny
authors.initials: S
authors.lastname: Thakkar
authors.affiliation: Department of Kinesiology, Temple University, Philadelphia, Pennsylvania;
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Babbitt
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Satoru
authors.initials: S
authors.lastname: Eguchi
authors.affiliation: Department of Kinesiology and Nutrition and Integrative Physiology Laboratory, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brown
authors.affiliation: Department of Kinesiology, Temple University, Philadelphia, Pennsylvania; Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania; and parkjy@temple.edu.
authors.forename: Joon-Young
authors.initials: JY
authors.lastname: Park
mesh_terms: D055252:Cell-Derived Microparticles / Q000378:metabolism*; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D015444:Exercise; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D063269:Mitochondrial Turnover; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics / Q000378:metabolism; D058246:Prehypertension / Q000097:blood / Q000378:metabolism*; D012039:Regional Blood Flow; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D019040:E-Selectin; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019038:Platelet Glycoprotein GPIb-IX Complex; D013267:Stilbenes; D014157:Transcription Factors; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: endothelial microparticle; exercise; mitochondrial biogenesis; shear stress