Jong-Shyan Wang

Different effects of strenuous exercise and moderate exercise on platelet function in men.

BackgroundPlatelets play an important role in the pathogenesis of cardiovascular diseases. It is also noticed that on one hand, regular exercise can reduce the risk of cardiovascular diseases, and on the other hand, vigorous exercise provokes sudden cardiac death. We therefore hypothesize that various intensities of exercise may affect platelet function differently. Methods and ResultsStrenuous and moderate exercise (about 50% to 55% of peak oxygen consumption, VO2peak) on a bicycle ergometer in 10 sedentary and 10 physically active healthy young men was executed on two separate occasions. Blood samples were collected before and immediately after exercise. A newly designed tapered parallel plate chamber was used to assess platelet adhesiveness. Platelet aggregation induced by ADP was evaluated by the percentage of reduction in single platelet count. β-Thromboglobulin (β-TG) and platelet factor 4 (PF4) were measured by ELISA. In addition, a similar study on 5 patients with stable angina were also conducted. Our results showed that (1) in the sedentary healthy group, platelet adhesiveness and aggregation were increased by strenuous exercise and depressed by moderate exercise; (2) in the active healthy group, platelet adhesiveness and aggregation were enhanced by severe exercise, whereas only aggregation was decreased by moderate exercise; (3) in the patients with stable angina, platelet adhesiveness and aggregation were enhanced by strenuous exercise and adhesiveness was suppressed by moderate exercise; (4) the degree of hemoconcentration induced by acute exercise tended to be related to the severity of exercise in all subjects; and (5) although severe exercise elevated β-TG and PF4, there were no significant changes in β-TG, PF4, and the ratio of β-TG to PF4 in healthy subjects after exercise. ConclusionsIt is concluded that platelet adhesiveness and aggregability may be sensitized by strenuous exercise in both healthy subjects and patients with stable angina. In contrast, platelet function can be suppressed significantly by moderate exercise in the healthy and tends to be depressed in patients with stable angina. The former may increase the risk of cardiac arrest and the latter may protect us from cardiovascular diseases. In addition, the effects of acute exercise tend to be more pronounced in the sedentary than in the active.

Effects of Exercise Training and Deconditioning on Platelet Function in Men

Platelets play an important role in the pathogenesis of cardiovascular disease. It has also been noticed that regular exercise can reduce the risk of cardiovascular disease. This is the first study to demonstrate that endurance exercise training may suppress platelet adhesiveness and aggregation and that deconditioning may reverse the training effects. Healthy male sedentary subjects were randomly divided into control and training groups. The trained men were trained on a bicycle ergometer at about 60% of maximal oxygen consumption for 30 minutes per day, 5 days per week for 8 weeks, then deconditioned for 12 weeks. During the experimental period, blood samples of the trained subjects were collected before and immediately after a progressive exercise test every 4 weeks. The same experiments were applied to the controls at the beginning of this study and 8 weeks thereafter. A tapered parallel-plate chamber was used to assess platelet adhesiveness. Platelet aggregation induced by ADP was evaluated by the percentage of reduction in single platelet count. Our results showed that (1) platelet adhesiveness and aggregability were increased by short-term strenuous exercise in both control and trained groups, but the enhancement of platelet aggregability was decreased after exercise training in the trained subjects; (2) at rest and immediately after strenuous exercise, platelet adhesiveness and aggregability were decreased by training, whereas they were unchanged in the control group; and (3) deconditioning reversed the training effects on resting and postexercise platelet adhesiveness and aggregability back to the pretraining state. These results suggest that platelet adhesiveness and aggregability may be depressed by exercise training but be reversed back to the pretraining state after deconditioning.

Aerobic interval training improves oxygen uptake efficiency by enhancing cerebral and muscular hemodynamics in patients with heart failure

BACKGROUND Abnormal ventilatory/hemodynamic responses to exercise contribute to functional impairment in patients with heart failure (HF). This study investigates how interval and continuous exercise regimens influence functional capacity by modulating ventilatory efficiency and hemodynamic function in HF patients. METHODS Forty-five HF patients were randomized to perform either aerobic interval training (AIT; 3-minute intervals at 40% and 80% VO(2peak)) or moderate continuous training (MCT; sustained 60% VO()for 30 min/day, 3 days/week for 12 weeks, or to a control group that received general healthcare (GHC). A noninvasive bio-reactance device was adopted to measure cardiac hemodynamics, whereas a near-infrared spectroscopy was employed to assess perfusion/O2 extraction in frontal cerebral lobe (∆[THb]FC/∆[HHb]FC) and vastus lateralis (∆[THb]VL/∆[HHb]VL), respectively. RESULTS Following the 12-week intervention, the AIT group exhibited higher oxygen uptake efficiency slope (OUES) and lower VE-VCO2 slope than the MCT and GHC groups. Furthermore, AIT, but not MCT, boosted cardiac output (CO) and increased ∆[THb]FC, ∆[THb]VL, and ∆[HHb]VL during exercise. In multivariate analyses, CO was the dominant predictor of VO(2peak). ∆[THb]FC and ∆[THb]VL, which modulated the correlation between CO and OUES, were significantly correlated with OUES. Simultaneously, ∆[THb]VL was the only factor significantly associated with VE-VCO2 slope. Additionally, AIT reduced plasma brain natriuretic peptide, myeloperoxidase, and interleukin-6 levels and increased the Short Form-36 physical/mental component scores and decreased the Minnesota Living with Heart Failure questionnaire score. CONCLUSIONS AIT effectively improves oxygen uptake efficiency by enhancing cerebral/muscular hemodynamics and suppresses oxidative stress/inflammation associated with cardiac dysfunction, and also promotes generic/disease-specific qualities of life in patients with HF.

Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-α in human tracheal smooth muscle cells: Involvement of MAPKs, NF-κB, p300, and histone acetylation

Tumor necrosis factor‐α (TNF‐α) has been shown to induce the expression of adhesion molecules in airway resident cells and contribute to inflammatory responses. Here, the roles of mitogen‐activated protein kinases (MAPKs) and NF‐κB in TNF‐α‐induced expression of vascular cell adhesion molecule (VCAM)‐1 were investigated in human tracheal smooth muscle cells (HTSMCs). TNF‐α‐enhanced expression of VCAM‐1 protein and mRNA as well as phosphorylation of p42/p44 MAPK, p38, and JNK were significantly attenuated by inhibitors of MEK1/2 (U0126), p38 (SB202190), and JNK (SP600125). Transfection with dominant negative mutants of MEK1/2, ERK1, ERK2, p38, and JNK attenuated TNF‐α‐induced VCAM‐1 expression. Furthermore, TNF‐α‐induced VCAM‐1 expression was significantly blocked by a selective NF‐κB inhibitor helenalin. TNF‐α‐stimulated translocation of NF‐κB into the nucleus and degradation of IκB‐α was blocked by helenalin, but not by U0126, SB202190, or SP600125. VCAM‐1 promoter activity was enhanced by TNF‐α in HTSMCs transfected with VCAM‐1‐Luc, which was inhibited by helenalin, U0126, SB202190, and SP600125. Most surprisingly, VCAM‐1 expression was also significantly blocked by a selective inhibitor of p300, curcumin. NF‐κB transcription factor and p300 were associated with the VCAM‐1 promoter, which was dynamically linked to histone H3 acetylation stimulated by TNF‐α, as determined by chromatin immunoprecipitation assay. Moreover, the resultant enhancement of VCAM‐1 expression increased the adhesion of polymorphonuclear cells (PMNs) to monolayer of HTSMCs, which was blocked by helenalin, U0126, SB202190, or SP600125. These results suggest that in HTSMCs, activation of MAPK pathways, NF‐κB, and p300 is essential for TNF‐α‐induced VCAM‐1 expression. J. Cell. Physiol. 207: 174–186, 2006.

Effect of Strenuous, Acute Exercise on α2-Adrenergic Agonist–Potentiated Platelet Activation

Vigorous exercise transiently increases the risk of primary cardiac arrest. Strenuous, acute exercise can also increase the release of plasma epinephrine. Previous investigations have indicated that epinephrine can potentiate platelet activation by activating platelet alpha2-adrenoceptors. This study investigated how strenuous, acute exercise affects alpha2-adrenergic agonist-potentiated platelet activation by closely examining 15 sedentary men who exercised strenuously on a bicycle ergometer. Before and immediately after exercise, platelet adhesiveness on fibrinogen-coated surfaces, [Ca2+]i in platelets, the number and affinity of alpha2-adrenergic sites on the platelet surface, and plasma catecholamine levels were determined. The results of this study can be summarized as follows: (1) The affinity of alpha2-adrenergic receptors on platelets decreases while the maximal binding number significantly increases after strenuous exercise, thereby correlating with the rise in plasma catecholamine levels. (2) Basal, clonidine-treated, ADP-treated, and clonidine plus ADP-treated adhesiveness and [Ca2+]i in platelets increased after strenuous exercise. (3) Strenuous exercise is associated with higher percentages of ADP- and clonidine plus ADP-enhanced platelet adhesiveness and [Ca2+]i than at rest. (4) The synergistic effects of clonidine on ADP-enhanced platelet adhesiveness and [Ca2+]i after strenuous exercise are much greater than those at rest. Therefore, we conclude that strenuous, acute exercise enhances platelet activation, possibly by altering the performance of platelet alpha2-adrenergic receptors, facilitating the ability of ADP-activated fibrinogen receptors, and enhancing fibrinogen binding to platelet fibrinogen receptors.

Effects of Exercise Training and Deconditioning on Platelet Aggregation Induced by Alternating Shear Stress in Men

Objective— Alternating shear stress, which resembles the flow condition in stenotic arteries, induces platelet aggregation. This study investigated how exercise training and deconditioning influence alternating shear-induced platelet aggregation (ASIPA) and clarify the mechanisms underlying ASIPA. Methods and Results— Thirty healthy male sedentary subjects were randomly divided into control and trained groups. The trained men were trained on a bicycle ergometer at ≈60% of maximal oxygen consumption for 30 minutes per day, 5 days per week for 8 weeks, and then were deconditioned for 8 weeks. The experimental results indicate the following: (1) short-term strenuous exercise increases the extent of ASIPA and is accompanied by increased the von Willebrand factor (vWF) binding and P-selectin expression on platelets in both the control and trained groups, whereas the enhancement of platelet function decreases after exercise training in trained subjects; (2) at rest and immediately after exercise, ASIPA and the vWF binding and P-selectin expression on platelets are reduced by training, but remain unchanged in the control group; and (3) deconditioning reverses the effects of training on resting and postexercise state. Conclusions— Exercise training suppresses the extent of ASIPA, probably by reducing vWF binding to platelets and P-selectin expression on platelets. However, deconditioning reverses the training effects.

Strenuous exercise promotes shear-induced thrombin generation by increasing the shedding of procoagulant microparticles from platelets

Vigorous exercise increases the risk of vascular thrombotic events. Shear stress enhances the shedding of procoagulant microparticles from platelets, and triggers thrombin generation (TG) in blood. This study explicates the manner in which strenuous exercise affects platelet-derived microparticles (PDMP) release and PDMP-mediated TG under various physio-pathological shear flows. Twenty-four sedentary healthy men performed a graded exercise test (up to VO2max) on a bicycle ergometer. At rest, immediately after and 2 hours after exercise, platelet-rich plasma (PRP) was exposed in a cone-and-plate viscometer to imitate static (0 dyne/cm2), physiological low (LS, 10 dyne/cm2) and pathological high (HS, 100 dyne/cm2) shear stresses ex vivo. The PDMP characteristics and dynamic TG were measured by two-colour flow cytometry and calibrated, automatic thrombinography, respectively. The results demonstrated that there is an increased level of total PDMP together with elevated peak height and rate of TG in PRP in response to both LS and HS conditions. Furthermore, HS, but not LS, promoted the binding of FV/Va or FVIII and the exposure of phosphatidylserine (PS) on platelets. Application of HS after strenuous exercise increased the factor (F)V/Va-/FVIII-/tissue factor-rich and PS-exposing PDMP counts, enhanced the PDMP-promoted peak height and rate of TG, as well as increased the ability of FV/Va or FVIII to bind to PDMP or platelets. However, the enhancement of HS-induced procoagulant activity reversed to the pre-exercise status 2 hours following this exercise. Therefore, we conclude that strenuous exercise modestly contributes to the acceleration of shear-induced TG by increasing the release of procoagulant microparticles from platelets.

Involvement of MAPKs and NF-κB in tumor necrosis factor α–induced vascular cell adhesion molecule 1 expression in human rheumatoid arthritis synovial fibroblasts

OBJECTIVE To investigate the roles of MAPKs and NF-kappaB in tumor necrosis factor alpha (TNFalpha)-induced expression of vascular cell adhesion molecule 1 (VCAM-1) in human rheumatoid arthritis synovial fibroblasts (RASFs). METHODS Human RASFs were isolated from synovial tissue obtained from patients with RA who underwent knee or hip surgery. The involvement of MAPKs and NF-kappaB in TNFalpha-induced VCAM-1 expression was investigated using pharmacologic inhibitors and transfection with short hairpin RNA (shRNA) and measured using Western blot, reverse transcriptase-polymerase chain reaction, and gene promoter assay. NF-kappaB translocation was determined by Western blot and immunofluorescence staining. The functional activity of VCAM-1 was evaluated by lymphocyte adhesion assay. RESULTS TNFalpha-induced VCAM-1 expression, phosphorylation of p42/p44 MAPK, p38 MAPK, and JNK, and translocation of NF-kappaB were attenuated by the inhibitors of MEK-1/2 (U0126), p38 (SB202190), JNK (SP600125), and NF-kappaB (helenalin) or by transfection with their respective shRNA. TNFalpha-stimulated translocation of NF-kappaB into the nucleus and NF-kappaB promoter activity were blocked by Bay11-7082, but not by U0126, SB202190, or SP600125. VCAM-1 promoter activity was enhanced by TNFalpha in RASFs transfected with VCAM-1-Luc, and this promoter activity was inhibited by Bay11-7082, U0126, SB202190, and SP600125. Moreover, up-regulation of VCAM-1 increased the adhesion of lymphocytes to the RASF monolayer, and this adhesion was attenuated by pretreatment with helenalin, U0126, SP600125, or SB202190 prior to exposure to TNFalpha or by anti-VCAM-1 antibody before the addition of lymphocytes. CONCLUSION In RASFs, TNFalpha-induced VCAM-1 expression is mediated through activation of the p42/p44 MAPK, p38 MAPK, JNK, and NF-kappaB pathways. These results provide new insights into the mechanisms underlying cytokine-initiated joint inflammation in RA and may inspire new targeted therapeutic approaches.

Effects of normoxic and hypoxic exercise regimens on cardiac, muscular, and cerebral hemodynamics suppressed by severe hypoxia in humans

Hypoxic preconditioning prevents cerebrovascular/cardiovascular disorders by increasing resistance to acute ischemic stress, but severe hypoxic exposure disturbs vascular hemodynamics. This study compared how various exercise regimens with/without hypoxia affect hemodynamics and oxygenation in cardiac, muscle, and cerebral tissues during severe hypoxic exposure. Sixty sedentary males were randomly divided into five groups. Each group (n = 12) received one of five interventions: 1) normoxic (21% O(2)) resting control, 2) hypoxic (15% O(2)) resting control, 3) normoxic exercise (50% maximum work rate under 21% O(2); N-E group), 4) hypoxic-relative exercise (50% maximal heart rate reserve under 15% O(2); H-RE group), or 5) hypoxic-absolute exercise (50% maximum work rate under 15% O(2); H-AE group) for 30 min/day, 5 days/wk, for 4 wk. A recently developed noninvasive bioreactance device was used to measure cardiac hemodynamics, and near-infrared spectroscopy was used to assess perfusion and oxygenation in the vastus lateralis (VL)/gastrocnemius (GN) muscles and frontal cerebral lobe (FC). Our results demonstrated that the H-AE group had a larger improvement in aerobic capacity compared with the N-E group. Both H-RE and H-AE ameliorated the suppression of cardiac stroke volume and the GN hyperemic response (Delta total Hb/min) and reoxygenation rate by acute 12% O(2) exposure. Simultaneously, the two hypoxic interventions enhanced perfusion (Delta total Hb) and O(2) extraction [Delta deoxyHb] of the VL muscle during the 12% O(2) exercise. Although acute 12% O(2) exercise decreased oxygenation (Delta O(2)Hb) of the FC, none of the 4-wk interventions influenced the cerebral perfusion and oxygenation during normoxic/hypoxic exercise tests. Therefore, we conclude that moderate hypoxic exercise training improves cardiopulmonary fitness and increases resistance to disturbance of cardiac hemodynamics by severe hypoxia, concurrence with enhancing O(2) delivery/utilization in skeletal muscles but not cerebral tissues.

Effects of Short-term Exercise on Female Platelet Function During Different Phases of the Menstrual Cycle

Previous studies have shown that premenopausal women have a low incidence of cardiovascular diseases, and that acute exercise affects male platelet function in an intensity-dependent manner. To investigate whether acute exercise affects female platelet function differently from males, sixteen sedentary women in the midfollicular phase or midluteal phase received strenuous or moderate exercise on a bicycle ergometer. Before and immediately after exercise, platelet adhesiveness, adenosine diphosphate-induced platelet aggregation and intracellular calcium concentration elevation, platelet cAMP and cGMP contents, urinary 11-dehydro-TXB2 and 6-keto-prostaglandin F1 alpha levels, and plasma nitric oxide metabolite level were determined. Our results showed no differences in exercise performance and in resting platelet function between two menstrual phases, with little change in urinary eicosanoid metabolites and platelet cAMP levels under all experimental conditions. In addition, for women in the midfollicular phase, (1) strenuous exercise increased platelet adhesiveness, adenosine-diphosphate-induced platelet aggregation, and intracellular calcium concentration elevation, whereas moderate exercise suppressed them; (2) moderate exercise enhanced plasma nitric oxide metabolite and platelet cGMP levels. In contrast, none of these platelet functions was affected by acute exercise in the midluteal phase. Therefore, we conclude that acute exercise affects female platelet function in an intensity-dependent manner in the midfollicular phase but not in the midluteal phase. The irresponsiveness of platelets to acute exercise in the luteal phase may partially explain why premenopausal women have a lower incidence of cardiovascular diseases than men.