ABSTRACT
AIMS: Adiponectin (adipo) and exercise training (ET) contribute to the maintenance of a normal vascular tone by influencing vascular NO bioavailability and concentration and function of circulating angiogenic cells (CAC). The molecular mechanisms are only partially understood. Aim of the present study was to elucidate the effects of adipo on CAC migration and the underlying signaling pathways. Furthermore, the impact of ET on adiponectin-mediated CAC migration was investigated. METHODS AND RESULTS: CACs were isolated from peripheral blood and exposed to different adipo concentrations. Adipo (5µg/ml) enhanced the ability of CACs to migrate following an SDF-1 gradient by 345%. This was associated with a significant increase in CXCR4 expression on the surface of CACs as compared to control (10.1 ± 1.5 vs. 33.2 ± 4.5% CXCR4 positive cells, p<0.05). Adiponectin-induced CAC migration and CXCR4-upregulation were mediated through adipo-receptor 1 (AdipoR1) and blocked by an inhibitor of PI3-kinase, p38MAP kinase and NFκb. Adipo-stimulated migration of CACs, CXCR4 expression and p38MAPK-activation is impaired in patients with coronary artery disease (CAD). ET over 4 weeks partially corrects adiponectin-stimulated CAC migration and CXCR4 expression in patients with CAD (n=10). No change was observed in the control group (n=10). CONCLUSION: Adipo improves the migratory capacity of CACs in response to SDF1, partially through an upregulation of CXCR4. This is mediated through a pathway that involves binding of adipo to the AdipoR1 and subsequent PI3kinase/p38MAPK/ NFκb activation. In addition ET corrects the adiponectin responsiveness of CACs, and thereby might promote endogenous repair of damaged endothelium.
Subject(s)
Adiponectin/pharmacology , Cell Movement/physiology , Coronary Artery Disease/metabolism , Neovascularization, Physiologic/physiology , Receptors, CXCR4/biosynthesis , p38 Mitogen-Activated Protein Kinases/physiology , Adiponectin/physiology , Adiponectin/therapeutic use , Aged , Cell Movement/drug effects , Cells, Cultured , Coronary Artery Disease/drug therapy , Coronary Artery Disease/physiopathology , Dose-Response Relationship, Drug , Exercise Test/methods , Female , Humans , Male , Neovascularization, Physiologic/drug effectsABSTRACT
UNLABELLED: Patients with advanced chronic heart failure (CHF) are characterized by progressive muscle wasting. The two E3-ligases Rnf28 and Atrogin-1 controlling the activation of the ubiquitinproteasome system might be of importance for the regulation of muscle size. Given the convincing effect of regular physical exercise training (ET) in CHF, it was the aim of the present trial to elucidate, whether ET affects both mentioned enzymes in CHF and whether this is associated with an increase in skeletal muscle mass. METHODS: 37 patients with severe CHF were randomized to 12 weeks of ET or sedentary lifestyle (control). The expression of Rnf28 and Atrogin-1 in the skeletal muscle was analyzed by RT-PCR and Western blotting. Skeletal muscle cross sectional area (CSA) was measured by computed tomography. RESULTS: In CHF patients ET led to a significant reduction in skeletal muscle mRNA transcription (from 14.3 ± 2.0 to 8.7 ± 1.4 arbitrary units; p<0.05 versus baseline and versus control for the change) and protein expression of Rnf28 (from 4.70 ± 1.35 to 2.84 ± 0.65 arbitrary units; p<0.05 versus baseline and versus control for the change). This was accompanied by a significant increase in total muscle CSA of both thighs (from 139.9 ± 5.2 to 149.2 ± 5.9 cm(2); p<0.05 versus baseline and versus control for the change). On the contrary, Atrogin-1 was not affected. CONCLUSION: In patients with advanced CHF, regular physical exercise training led to a decrease in Rnf28 expression in the skeletal muscle. This was linked to an increase in skeletal muscle cross sectional area, supporting the notion that ET has anti-catabolic properties in CHF.
Subject(s)
Exercise Test/methods , Exercise/physiology , Gene Expression Regulation, Enzymologic , Heart Failure/enzymology , Muscle Proteins/biosynthesis , Muscle, Skeletal/enzymology , Ubiquitin-Protein Ligases/biosynthesis , Chronic Disease , Female , Heart Failure/diagnostic imaging , Humans , Male , Middle Aged , Muscle, Skeletal/diagnostic imaging , Organ Size/physiology , Radiography , Sedentary Behavior , Tripartite Motif ProteinsABSTRACT
OBJECTIVE: Exercise training partially corrects endothelial dysfunction in patients with coronary artery disease (CAD). Growth factors like vascular endothelial growth factor (VEGF) as well as erythropoietin (EPO) are known to modulate the bioavailability of nitric oxide and, thereby, contribute to the maintenance of a normal vascular tone. The aim of the present study was to determine the impact of 4 weeks of exercise training on circulating growth factors and to elucidate their involvement in the training-induced changes in vasomotion in patients with CAD. METHODS AND RESULTS: A total of 39 patients were enrolled (training group: n = 20; control group: n = 19). At start of study and after 4 weeks, average peak flow velocity (APV) of the left internal mammary artery (LIMA) in response to acetylcholine was measured invasively in the treatment and control groups. Serum concentrations of VEGF and EPO were determined by enzyme-linked immunosorbent assay. After exercise training, LIMA APV in response to acetylcholine was increased by 93% (from 69 ± 17% at start of study to 133 ± 16% at 4 weeks, p < 0.01 vs. start of study and control). At start of study, there was no association between any of the vascular growth factors and endothelial function. However, after exercise training a close correlation was apparent between the acetylcholine-induced change in APV and EPO (r = 0.69, p < 0.01) and VEGF (r = 0.76, p < 0.01) serum concentrations. In the control group, these correlations were not evident and there was no change in endothelial function either. CONCLUSION: Exercise training improves agonist-mediated endothelium-dependent vasodilatation in CAD, partially through a restoration of the endothelial response to EPO and VEGF.
Subject(s)
Coronary Artery Disease/therapy , Endothelium, Vascular/metabolism , Erythropoietin/blood , Exercise Therapy , Mammary Arteries/metabolism , Vascular Endothelial Growth Factor A/blood , Vasodilation , Aged , Analysis of Variance , Blood Flow Velocity , Chi-Square Distribution , Coronary Artery Disease/blood , Coronary Artery Disease/physiopathology , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Enzyme-Linked Immunosorbent Assay , Female , Germany , Humans , Linear Models , Male , Mammary Arteries/drug effects , Mammary Arteries/physiopathology , Middle Aged , Regional Blood Flow , Time Factors , Treatment Outcome , Vasodilation/drug effects , Vasodilator Agents/administration & dosageABSTRACT
BACKGROUND: In chronic heart failure (CHF), cardiac cachexia is often associated with the terminal stage of this disease. In animal studies it has been demonstrated that myostatin, a key regulator of skeletal muscle mass, is elevated in advanced stages of this syndrome. DESIGN: The aim of the present study was to investigate the expression of myostatin in patients with late stage CHF (NYHA IIIb) in comparison to healthy subjects. Furthermore the effects of physical exercise on myostatin were analyzed. METHODS: Twenty-four patients were either randomized to a sedentary control group (CHF-S) or exercise training (CHF-E). At baseline and after 12 weeks mRNA and myostatin protein in the peripheral skeletal muscle as well as myostatin serum concentration were measured. Furthermore 12 age-matched healthy men were compared to all patients at baseline (HC). RESULTS: CHF patients showed a two-fold increase of myostatin mRNA (p = 0.05) and a 1.7-fold (p = 0.01) augmentation of protein content in skeletal muscle compared to healthy subjects. In late-stage CHF, exercise training led to a 36% reduction of the mRNA and a 23% decrease of the myostatin protein compared to baseline. The serum concentration of myostatin revealed no significant alteration between the groups. CONCLUSION: In the skeletal muscle, myostatin increases significantly in the course of CHF. The observed effects of a significant reduction of myostatin in skeletal muscle after 12 weeks of exercise training demonstrate the reversibility of molecular changes that might be able to halt the devastating process of muscle wasting in chronic heart failure.
Subject(s)
Exercise Therapy , Heart Failure/therapy , Muscle, Skeletal/metabolism , Myostatin/blood , Aged , Bicycling , Biomarkers/blood , Chi-Square Distribution , Chronic Disease , Down-Regulation , Germany , Heart Failure/blood , Heart Failure/genetics , Heart Failure/physiopathology , Humans , Male , Middle Aged , Myostatin/genetics , RNA, Messenger/metabolism , Sedentary Behavior , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVES: The concept of neovascularization in response to tissue ischemia was recently extended by the finding of postnatal vasculogenesis through circulating endothelial progenitor cells (EPCs). The aim of this study was to assess the role of acute ischemia for EPC mobilization in patients with peripheral arterial occlusive disease (PAOD) and in healthy volunteers. METHODS: The number of circulating EPCs was analyzed by flow cytometry in PAOD patients (n = 23) with exercise-induced limb ischemia for up to 72 h after a maximal treadmill test and in healthy volunteers (n = 17) who underwent a 15-min suprasystolic occlusion of one lower extremity to induce limb ischemia. Plasma concentrations of vascular endothelial growth factor, basic fibroblast growth factor, tumor necrosis factor-α, and granulocyte macrophage-colony stimulating factor were determined by ELISA. RESULTS: EPCs (CD 34 pos/KDRpos) increased significantly in both PAOD patients from 82 ± 20 to 256 ± 52 (P < 0.05) and healthy volunteers from 144 ± 39 to 590 ± 61 cells per 1 million events (P < 0.05) in response to induced ischemia, with a maximum after 24 h and returned to baseline within 72 h. The relative increase in EPC numbers was significantly lower in patients with PAOD as compared with healthy volunteers (P < 0.05). Plasma levels of vascular endothelial growth factor increased from 27.4 ± 3.1 to 126.4 ± 12 pg/ml in patients with PAOD (P < 0.05) and from 30.7 ± 6.1 to 134.1 ± 12.4 pg/ml in healthy volunteers (P < 0.05). CONCLUSION: Both patients with symptomatic PAOD and healthy volunteers respond to a single episode of limb ischemia with a time-dependent increase in circulating EPCs. The increase of EPC numbers in response to ischemia is reduced when vascular disease is present, underlining the reduced vasculogenic potential of patients with PAOD.
Subject(s)
Endothelial Cells/pathology , Exercise Tolerance , Ischemia/complications , Lower Extremity/blood supply , Peripheral Arterial Disease/complications , Stem Cells/pathology , Adult , Biomarkers/blood , Case-Control Studies , Cell Movement , Cells, Cultured , Endothelial Cells/metabolism , Enzyme-Linked Immunosorbent Assay , Exercise Test , Female , Fibroblast Growth Factor 2/blood , Flow Cytometry , Germany , Granulocyte-Macrophage Colony-Stimulating Factor/blood , Humans , Ischemia/blood , Ischemia/pathology , Ischemia/physiopathology , Male , Middle Aged , Neovascularization, Physiologic , Peripheral Arterial Disease/blood , Peripheral Arterial Disease/pathology , Peripheral Arterial Disease/physiopathology , Prospective Studies , Stem Cells/metabolism , Time Factors , Tourniquets , Tumor Necrosis Factor-alpha/blood , Vascular Endothelial Growth Factor A/bloodABSTRACT
BACKGROUND: The full impact of statins on patients with chronic heart failure (CHF) is unknown. Therefore, we aimed to evaluate the pleiotropic effects of rosuvastatin on vascular and tissue regeneration, its impact on endothelial function and hemodynamics in CHF. METHODS: Forty-two patients with CHF (LVEF 30±1%) were randomized to 12 weeks of oral rosuvastatin (40 mg/d) or placebo. At baseline and at 12 weeks, VEGF and oxidized LDL (oxLDL) were assessed by ELISA. Circulating endothelial progenitor cells (CPCs) were quantified using FACS. CPC function was determined by matrigel assay. Number of CD34(+) stem cells and capillary density were measured in skeletal muscle (SM). Flow-mediated dilatation (FMD) and left ventricular (LV) function were determined by ultrasound. RESULTS: Rosuvastatin increased VEGF by +43% (p=0.004 vs. placebo) and decreased oxLDL by -27% (p=0.04 vs. placebo). This was associated with an elevation in CPC count by +224% (p=0.04 vs. placebo) and an augmentation of CPC integrative capacity by +91% (p=0.03 vs. placebo). Capillary density increased by +14% (p<0.001 vs. placebo), which was associated with an enhanced homing of CD34(+) stem cells. Rosuvastatin improved FMD by +163% (p<0.001 vs. placebo) and enhanced ejection fraction by +27% (p<0.001 vs. placebo). CONCLUSION: In CHF, rosuvastatin activates CPCs that contribute to neovascularisation and to the enhancement of endothelial function. Correction of vascular abnormalities leads in part to an increase in LV function. Therefore, rosuvastatin's non-lipid effects may have the potential to promote endogenous tissue regeneration and improve LV performance in CHF.
Subject(s)
Endothelium, Vascular/drug effects , Fluorobenzenes/administration & dosage , Heart Failure/drug therapy , Neovascularization, Physiologic/drug effects , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , Ventricular Remodeling/drug effects , Administration, Oral , Aged , Cells, Cultured , Chronic Disease , Double-Blind Method , Drug Administration Schedule , Endothelium, Vascular/physiology , Female , Heart Failure/physiopathology , Humans , Male , Middle Aged , Neovascularization, Physiologic/physiology , Rosuvastatin Calcium , Ventricular Remodeling/physiologyABSTRACT
BACKGROUND: Attenuated peripheral perfusion in patients with advanced chronic heart failure (CHF) is partially the result of endothelial dysfunction. This has been causally linked to an impaired endogenous regenerative capacity of circulating progenitor cells (CPC). The aim of this study was to elucidate whether exercise training (ET) affects exercise intolerance and left ventricular (LV) performance in patients with advanced CHF (New York Heart Association class IIIb) and whether this is associated with correction of peripheral vasomotion and induction of endogenous regeneration. METHODS AND RESULTS: Thirty-seven patients with CHF (LV ejection fraction 24+/-2%) were randomly assigned to 12 weeks of ET or sedentary lifestyle (control). At the beginning of the study and after 12 weeks, maximal oxygen consumption (Vo(2)max) and LV ejection fraction were determined; the number of CD34(+)/KDR(+) CPCs was quantified by flow cytometry and CPC functional capacity was determined by migration assay. Flow-mediated dilation was assessed by ultrasound. Capillary density was measured in skeletal muscle tissue samples. In advanced CHF, ET improved Vo(2)max by +2.7+/-2.2 versus -0.8+/-3.1 mL/min/kg in control (P=0.009) and LV ejection fraction by +9.4+/-6.1 versus -0.8+/-5.2% in control (P<0.001). Flow-mediated dilation improved by +7.43+/-2.28 versus +0.09+/-2.18% in control (P<0.001). ET increased the number of CPC by +83+/-60 versus -6+/-109 cells/mL in control (P=0.014) and their migratory capacity by +224+/-263 versus -12+/-159 CPC/1000 plated CPC in control (P=0.03). Skeletal muscle capillary density increased by +0.22+/-0.10 versus -0.02+/-0.16 capillaries per fiber in control (P<0.001). CONCLUSIONS: Twelve weeks of ET in patients with advanced CHF is associated with augmented regenerative capacity of CPCs, enhanced flow-mediated dilation suggestive of improvement in endothelial function, skeletal muscle neovascularization, and improved LV function. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00176384.