The prevalence and impact of sarcopenia in older cardiac patients undergoing inpatient cardiac rehabilitation - results from a prospective, observational cohort pre-study.

BACKGROUND: The prevalence of sarcopenia and its impact in older patients undergoing inpatient cardiac rehabilitation (iCR) after cardiac procedure has been insufficiently studied. The main aim of this study was to evaluate the prevalence of sarcopenia and quantify the functional capacity of older sarcopenic and non-sarcopenic patients participating in iCR. METHODS: Prospective, observational cohort study within the framework of the ongoing multicenter prehabilitation study "PRECOVERY". A sample of 122 patients ≥75 years undergoing iCR after cardiac procedure were recruited in four German iCR facilities and followed up 3 months later by telephone. At iCR (baseline), the Strength, Assistance with walking, Rise from a chair, Climb stairs and Falls (SARC-F) questionnaire was used to identify sarcopenic patients. In addition, Katz-Index, Clinical Frailty Scale (CFS), handgrip strength (HGS), Short Physical Performance Battery (SPPB) and 6-minute walk distance (6MWD) measured functional capacity and frailty at baseline. Outcomes were prevalence of sarcopenia and the correlation of sarcopenia to functional capacity and frailty at baseline as well as the SARC-F score at follow-up. The Wilcoxon test was applied for pre-post-test analysis. Correlation between sarcopenia and 6MWD, SPPB score and HGS was tested with the eta coefficient with one-way ANOVA. RESULTS: Complete assessments were collected from 101 patients (79.9 ± 4.0 years; 63% male). At baseline, the mean SARC-F score was 2.7 ± 2.1; 35% with sarcopenia. Other baseline results were Katz-Index 5.7 ± 0.9, CFS 3.2 ± 1.4, HGS 24.9 ± 9.9 kg, SPPB score 7.5 ± 3.3 and 6MWD 288.8 ± 136.5 m. Compared to baseline, fewer patients were sarcopenic (23% versus 35%) at follow-up. In the subgroup of sarcopenic patients at baseline (n = 35), pre-post comparison resulted in a significant SARC-F improvement (p = 0.017). There was a significant correlation between sarcopenia measured by SARC-F and poor results in the assessments of functional capacity (p < 0.001; r > 0.546). CONCLUSIONS: The prevalence of sarcopenia in older patients at iCR after cardiac procedure is high (35%) and remains high at follow-up (23%). Sarcopenia screening is important since the diagnosis of sarcopenia in these patients correlates significantly with poor functional capacity. The results indicate that these patients may benefit from prehabilitation aimed at improving perioperative outcomes, increasing functional capacity and mitigating adverse effects. TRIAL REGISTRATION: German Clinical Trials Register (DRKS; http://www.drks.de ; DRKS00032256). Retrospectively registered on 13 July 2023.

Evidence for Training-Induced Changes in miRNA Levels in the Skeletal Muscle of Patients With Type 2 Diabetes Mellitus.

Physical training can improve glycemic control in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanisms are not entirely clear. An interesting piece of the puzzle could be the regulation of micro-RNAs (miRNAs). They are important modulators of protein expression. Some miRNAs were found to be both linked to poor glycemic control/insulin resistance (with evidence from in vivo and/or in vitro studies) and dysregulated in the skeletal muscle of T2DM patients. This pilot study examines whether a 3-month endurance training program [three times a week, 70-80% peak heart rate (HRpeak)] can down-regulate their levels in T2DM men (n = 7). One skeletal muscle biopsy sample was obtained from each patient at T1 (6 weeks pre-intervention), one at T2 (1 week pre-intervention) and one at T3 (3-4 days post-intervention). miRNA-27a-3p, -29a-3p, -29b-3p, -29c-3p, -106b-5p, -135a-5p, -143-3p, -144-3p, -194-5p, and - 206 levels were determined by RT-qPCR. Friedman ANOVA and post-hoc tests showed that miRNA-29b-3p, -29c-3p and -135a-5p levels were significantly reduced post-training (T3 vs. T2 and/or T1). Glycated hemoglobin (HbA1c) and HOMA insulin resistance index did not change significantly. However, HbA1c was reduced in 6 of 7 patients post-training. Furthermore, Spearman's rank correlation analyses with all values from all time points showed significant negative associations between miRNA-29c-3p, -106b-5p, -144-3p and -194-5p levels and cardiorespiratory fitness (VO2peak). The study results imply that regular exercise and improving one's physical fitness is helpful for the regulation of skeletal muscle miRNAs in T2DM patients. Whether or not changes in the miRNA profile can affect the clinical situation of T2DM patients warrants further research.

Effects of exercising before breakfast on the health of T2DM patients-A randomized controlled trial.

This is the first study to examine whether training before breakfast in the overnight-fasted state is more effective in improving the health of patients with type 2 diabetes mellitus (T2DM) than after breakfast in the fed state. Thirty T2DM patients (60 ± 8 years, 33.7 ± 4.6 kg/m2 ) were randomly assigned to the F group (training in the overnight-fasted state (n = 15)) and to the C group (training in the fed state (control group, n = 15)). All patients completed an 8-week combined endurance/strength training program. Physical training significantly increased time to physical exhaustion during an endurance test (+10.4%), power output during strength tests (chest presses: +36.7% and seated rows: +37.8%), and fat-free mass (+1.7 kg). Body fat mass (-1.9 kg), glycated hemoglobin (HbA1c) values (absolute change: -0.3%), serum insulin values (-2.5 microU/mL), the homeostatic model assessment for insulin resistance (HOMA-IR) index (-1.1), and circulating triglyceride levels (-31 mg/dL) decreased significantly from pre- to post-training. The training had no effect on body mass index, serum fasting glucose, total cholesterol, low-density lipoprotein/high-density lipoprotein ratio or interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)α levels. Analyses of variance revealed no time × group interaction for any variable (P > .05). The training was effective in improving the health of T2DM patients. However, the preliminary study's data do not provide any evidence that the nutritional state (overnight-fasted or fed) in regular physical training plays a significant role for training-induced adaptations in T2DM patients. Full trials (using other training protocols as well) should be conducted to gain further knowledge about the relevance of pre-exercise breakfast ingestion.

Endurance training alters YKL40, PERM1, and HSP70 skeletal muscle protein contents in men with type 2 diabetes mellitus.

BACKGROUND: The fight against type 2 diabetes mellitus (T2DM) is tremendously challenging. This pilot study investigates whether endurance training (3 times per week for 3 months, moderate intensity) can change the skeletal muscle protein contents of chitinase-3-like protein-1 (YKL40), peroxisome proliferator-activated receptor y coactivator-1 and estrogen-related receptor-induced regulator in muscle-1 (PERM1) and heat-shock protein-70 (HSP70), which have been discussed as novel therapeutically relevant targets. METHODS: Muscle biopsies were obtained from overweight/obese men with T2DM (n = 7, years = 63 ± 9) at T1 (6 weeks pre-training), T2 (1 week pre-training) and T3 (3 to 4 days post-training). The protein levels of YKL40, PERM1, and HSP70 were determined by immunohistochemistry. RESULTS: YKL40, PERM1, and HSP70 were significantly upregulated following endurance training (T2-T3: +103%, +61%, +89%, p = 0.012, p = 0.010, p = 0.028). There was a fiber type-specific distribution of HSP70 with increased protein contents in type I fibers. A significant change in the fiber type distribution with an increase in type I fibers and a decrease in type II fibers was observed post-training. There were no significant differences for YKL40, PERM1, HSP70, or the fiber type distribution between T1 and T2. CONCLUSION: The training-induced upregulation of YKL40, PERM1, and HSP70 could help manage the diabetic disease and reduce its complications.

Moderate endurance training (marathon-training) - effects on immunologic and metabolic parameters in HIV-infected patients: the 42 KM cologne project.

BACKGROUND: Improved treatment options of HIV have resulted in regular physical activities of many HIV-infected patients. However, data on effects of sports in HIV-patients are scarce. METHODS: 21 HIV-infected persons were monitored prospectively while preparing for a marathon run. Multiple parameters with regard to immunology, quality of life and metabolism were measured at 4 time points (at baseline 1 year before the marathon run, 3 and 6 months after beginning of training, and immediately before marathon). RESULTS: 13 out of 21 participants completed the marathon (12 male, 1 female; median age 42 years [27-50]; CD4 = 620/µl [146-1268]; 11 were on ART since 3.5 years [1-7]). 8 participants ceased training early. All reasons for stopping (besides one pre-existing metatarsal fracture) were not regarded as training-related (e.g. time limitation n = 3; newly diagnosed anal cancer n = 1; personal reasons/unknown n = 3). We observed a significant increase in absolute CD4-T-cells (620/µl [146-1268] vs. 745 [207-1647]; p = 0.001) with simultaneous decrease of CD4-T-cell apoptosis (53% [47-64] vs. 32% [14-42]); p < 0.01). No effects on viral load independent of ART occurred. Systolic blood pressure and cholesterol improved significantly, although moderate and normal at baseline (cholesterol 185 mg/dl [98-250] vs. 167 [106-222], p = 0.02; RRsys 125 mmHg [100-145] vs. 120 [100-140], p = 0.01). Blood count, liver enzymes, creatinine and CK remained unchanged. CONCLUSIONS: The results of this pilot study indicated improved metabolic and immunologic parameters in HIV-infected patients undergoing moderate endurance training. Although training effects or ART cannot be ultimately separated as underlying mechanisms, we conclude that marathon training is safe for HIV-infected patients and potentially improves general health. TRIAL REGISTRATION: DRKS00011592 (retrospectively registered on February 9th 2017).

Influence of endurance training on skeletal muscle mitophagy regulatory proteins in type 2 diabetic men.

BACKGROUND: Mitophagy is a form of autophagy for the elimination of mitochondria. Mitochondrial content and function are reduced in the skeletal muscle of patients with type 2 diabetes mellitus (T2DM). Physical training has been shown to restore mitochondrial capacity in T2DM patients, but the role of mitophagy has not been examined in this context. This study analyzes the impact of a 3-month endurance training on important skeletal muscle mitophagy regulatory proteins and oxidative phosphorylation (OXPHOS) complexes in T2DM patients. METHODS: Muscle biopsies were obtained from eight overweight/obese T2DM men (61±10 years) at T1 (6 weeks pre-training), T2 (1 week pre-training), and T3 (3 to 4 days post-training). Protein contents were determined by Western blotting. RESULTS: The training increased mitochondrial complex II significantly (T2-T3: +29%, p = 0.037). The protein contents of mitophagy regulatory proteins (phosphorylated form of forkhead box O3A (pFOXO3A), mitochondrial E3 ubiquitin protein ligase-1 (MUL1), Bcl-2/adenovirus E1B 19-kD interacting protein-3 (BNIP3), microtubule-associated protein 1 light chain-3B (the ratio LC3B-II/LC3B-I was determined)) did not differ significantly between T1, T2, and T3. CONCLUSIONS: The results imply that training-induced changes in OXPHOS subunits (significant increase in complex II) are not accompanied by changes in mitophagy regulatory proteins in T2DM men. Future studies should elucidate whether acute exercise might affect mitophagic processes in T2DM patients (and whether a transient regulation of mitophagy regulatory proteins is evident) to fully clarify the role of physical activity and mitophagy for mitochondrial health in this particular patient group.

Hypoxia and Hyperoxia Affect Serum Angiogenic Regulators in T2DM Men during Cycling.

Exercise-induced transient increases in pro-angiogenic regulators can promote angiogenesis.This pilot study aims to analyze the potential of exercise to positively affect angiogenic regulators in patients with type 2 diabetes mellitus (T2DM), who often exhibit abnormal angiogenesis, under different environmental conditions. 9 overweight/obese men with uncomplicated T2DM (8 took anti-diabetic drugs) performed submaximal cycling for 40 min in normoxia (≈21 vol%O2), hypoxia (≈14 vol%O2) and during alternating hypoxia/hyperoxia (≈14 vol%O2/≈30 vol%O2, 5-min intervals) (3×3 crossover design). Serum pro-angiogenic vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, MMP-9 and anti-angiogenic endostatin were quantified using enzyme-linked immunosorbent assay (ELISA) kits. Non-parametric statistical tests (Wilcoxon, Friedman analysis of variance) were applied. VEGF increased significantly from pre- to post-exercise with hypoxia and hypoxia/hyperoxia. MMP-2 increased significantly in all experimental runs, while MMP-9 only increased significantly with hypoxia and hypoxia/hyperoxia. Endostatin increased significantly with normoxia and hypoxia. However, the magnitude of changes did not differ significantly between conditions. Capillary blood lactate was significantly lower following cycling with hypoxia/hyperoxia than with hypoxia alone. Although differences in subjective ratings of perceived exertion failed significance, 7 subjects were less exerted with hypoxia/hyperoxia than with hypoxia. Submaximal cycling with hypoxia or alternating hypoxia/hyperoxia may induce a more reliable up-regulation of pro-angiogenic regulators compared with normoxia, while hypoxia/hyperoxia may be better tolerated than hypoxia alone.

Effects of Endurance Training on the Skeletal Muscle Nitric Oxide Metabolism in Insulin-Independent Type 2 Diabetic Men-A Pilot Study.

BACKGROUND: Increases in the amount of inducible nitric oxide synthase (iNOS) protein and abnormal production of nitric oxide (NO) in skeletal muscle have been suggested to be associated with peripheral insulin resistance in patients with type 2 diabetes mellitus (T2DM). This pilot study analyzed whether a 3-month endurance training can affect iNOS protein and NO metabolite levels in the vastus lateralis muscle of insulin-independent T2DM men, thereby affecting the patients` glycemic control. Furthermore, serum molecules, which have been shown to activate iNOS protein expression in in vitro experiments, were quantified. METHODS: Eight overweight/obese T2DM men (years = 61 ± 10) participated in the study. Muscle biopsies and venous blood collections were performed at T1 (6 weeks before training), T2 (1 week before training), and T3 (3 to 4 days after training). Protein contents (iNOS) were determined by Western blotting, nitrite concentrations by chemiluminescence, and serum molecule levels by enzyme-linked immunosorbent assay kits. RESULTS: The training reduced iNOS protein contents significantly (T2-T3: approximately -31%, P = 0.018). Nitrite concentrations as well as fasting glucose and HbA1c decreased, but not significantly. Serum tumor necrosis factor-α, thiobarbituric acid-reactive substances (lipid peroxidation as an indirect measure of reactive oxygen species), lipopolysaccharide binding protein, interferon-γ, and interleukin-1ß showed no significant changes. CONCLUSIONS: The data indicate that the endurance training performed in the present study can reduce iNOS protein contents in insulin-independent T2DM men. Future studies should identify key molecules in iNOS regulation in vivo and fully clarify whether iNOS downregulation can help improve insulin sensitivity in T2DM patients in the long term.

Phosphorylation of myocardial eNOS is altered in patients suffering from type 2 diabetes.

The present study investigated whether endothelial nitric oxide synthase (eNOS) activation may be dysregulated in cardiac tissue of patients suffering from type 2 diabetes (T2D). We performed immunohistochemical measurements of translocated eNOS activation as well as eNOS phosphorylation at Ser1177, Thr495, Ser 635, Ser114, and of the protein kinase B (Akt) in isolated right atrial trabeculae of patients undergoing cardiac bypass or valve surgery with (n = 12, 68.1 ± 2.5 yr) and without T2D (n = 12, 64.7 ± 2.7 yr). In addition, we investigated oxidative (8-isoprostane) and nitrosative stress markers (nitrotyrosine) as well as the effect of pharmacological stimulation of angiotensin (AT)-receptors on eNOS-phosphorylation. Translocation-dependent eNOS activation was similar in both groups. The same holds true for eNOS phosphorylation at Ser114. eNOS phosphorylation at Ser635 was significantly increased, whereas eNOS phosphorylation of Ser1177 was significantly decreased in the diabetic group paralleled by a decrease in phosphorylation of Akt and Thr495. These alterations were accompanied by a significant decrease in nitrotyrosine. After application of angiotensin II (10 µM, 2 min) for investigation of the AT-receptor-dependent eNOS stimulation, we did not find differences between the increases in eNOS Ser1177-phosphorylation in the nondiabetic (+39.7 ± 23.5%) and in the diabetic group (32.22 ± 11.45%). A simultaneous increase in Akt phosphorylation could not be observed. The present study indicates that T2D goes along with a decrease in eNOS phosphorylation at Ser1177 under basal conditions in cardiac tissue. Whether this may be attributed to the insulin resistance of cardiac muscle has to be further investigated. Receptor-stimulated eNOS activation still works at least for angiotensin II-dependent eNOS activation.

Increased Ca2+ sensitivity of myofibrillar tension in ischaemic vs dilated cardiomyopathy.

1. There is evidence that different aetiologies of heart failure, especially ischaemic vs dilated cardiomyopathy (ICM and DCM, respectively), may influence the prognosis of patients with this disease. Patients with ICM have a worse prognosis than those with DCM; the mechanisms underlying this difference have not yet been clarified. The aim of the present study was to investigate whether there are changes in myofibrillar function depending on the aetiology of human heart failure. 2. Ca(2+) -dependent tension (DT) and actomyosin ATPase activity (MYO) in Triton X-skinned fibre preparations of the left ventricular myocardium from patients with heart failure due to ICM (n=5) and DCM (n=5) were measured. Tension-dependent ATP consumption was calculated by the ratio of DT and MYO ('tension cost'). Non-failing myocardium (NF) from donor hearts, which could not be transplanted because of technical reasons, was evaluated as a control. 3. Although DT was reduced, the myofibrillar Ca(2+) sensitivity of DT and MYO, as well as tension cost, were increased in preparations from ICM and DCM myocardium compared with NF. The Ca(2+) sensitivity of DT and MYO was significantly increased in ICM compared with DCM preparations, resulting in more economic cross-bridge cycling in ICM than in DCM. 4. In conclusion, ICM is associated with an increased Ca(2+) sensitivity of myofibrillar tension and ATPase activity accompanied by decreased tension cost compared with DCM. Thus, the worse prognosis associated with ICM does not seem to be due to differences in myofibrillar function.

Human mesenchymal stem cells: Influence of oxygen pressure on proliferation and chondrogenic differentiation in fibrin glue in vitro.

Tissue engineering using biomaterials is a promising solution for cartilage replacement. The purpose of this study was to investigate whether the fibrin sealant Tissucol(R) provides a suitable scaffold for re-implanting stem cells during chondrogenic replacement therapy. Pluripotent stem cells were isolated from adult human bone marrow (hMSCs), cultured and characterized by FACS (CD105+/CD106+, CD45-/CD14-/CD34-). A large-holed porous hMSC-containing fibrin matrix was built that allowed hMSCs to survive throughout the period of culture (42 days) in either proliferation or chondrogenic differentiation medium under normoxic (21% O2) or hypoxic (3% O2) conditions. Morphology (as determined by electron microscopy) and proliferation (Ki67 staining) of the embedded hMSCs did not markedly vary under normoxic and hypoxic culture even after 42 days in culture. The stem cell marker Oct-4 was expressed during the whole culture period. Under chondrogenic differentiation conditions, especially under hypoxic conditions, we observed rounded chondrocyte-like cell types and a chondral phenotype assessed by mRNA expression of collagen II and Alcian blue staining. hMSCs seeded into large-holed porous preparations of Tissucol survive, proliferate and keep their stem cell character. Furthermore, culturing the cells in a corresponding medium induces chondrogenic differentiation, which could be remarkably and significantly enhanced under hypoxic conditions.

[Third generation beta-blockers: current state of research on vasodilating beta-blockers]. / Betablocker der 3. Generation: Stand der Forschung zu den Betablockern mit vasodilatierenden Zusatzeigenschaften.

Nebivolol (Nomexor) is a third generation, vasodilating beta-blocker with a high beta(1)-adrenoceptor selectivity. Nebivolol acts as an agonist at the beta(3) adrenoceptor as well as the estrogen receptor thereby releasing nitric oxide in blood vessels via eNOS. Pleiotropic effects of nebivolol furthermore include a positive influence on cholesterol and triglycerides and a decrease in thrombocyte activity. Nebivolol is recommended in the guidelines of the European cardiac society (ESC) for patients with metabolic syndrome. Nebivolol's main properties in combination with its broad range of beneficial pleiotropic effects allow it to be clearly distinguished from other second and third generation beta-blockers.

Angiogenic and vascular modulation by extracellular matrix cleavage products.

In the last fifteen years different extracellular matrix proteins and cleavage products have been identified. These molecules possess the ability to regulate vascular development, repair and function. However, the concept is still inconsistent and only partially understood. In this review, we will focus on angiogenesis regulation by extracellular matrix processing. Therefore, possible regulatory mechanisms in vascular biology controlled by different cleavage products of basement membrane proteins (e.g. endostatin and tumstatin, endorepellin), their activation by proteases and inhibitors, such as matrix metalloproteases (MMPs), cathepsins, tissue inhibitors of MMPs and cystatin, will be reviewed. Up to now there is only limited knowledge about the situations, under which different ECM cleavage products will be released and produced by proteases. Beside vascular growth and the formation of new blood vessels, it is also important to pay attention to the implication of the mentioned proteins in the vascular repair process. Physical exercise and its angio-regulatory potentials have become in the focus in recent years. We will therefore discuss physical exercise and its effects on the mentioned molecules regarding angiogenic inductions. Until today it remains to be clearly stated, which impact might be achieved by matrix cleavage products with respect to the regulation of vascular progenitor cells and their possible therapeutical role in support of vascular repair mechanisms. Furthermore, the current knowledge of the functional role of ECM in the vascular system is highlighted.

Exercise-induced stem cell activation and its implication for cardiovascular and skeletal muscle regeneration.

A number of publications have provided evidence that exercise and physical activity are linked to the activation, mobilization, and differentiation of various types of stem cells. Exercise may improve organ regeneration and function. This review summarizes mechanisms by which exercise contributes to stem cell-induced regeneration in the cardiovascular and the skeletal muscle system. In addition, it discusses whether exercise may improve and support stem cell transplantation in situations of cardiovascular disease or muscular dystrophy.

Integrin-linked kinase stabilizes myotendinous junctions and protects muscle from stress-induced damage.

Skeletal muscle expresses high levels of integrin-linked kinase (ILK), predominantly at myotendinous junctions (MTJs) and costameres. ILK binds the cytoplasmic domain of beta1 integrin and mediates phosphorylation of protein kinase B (PKB)/Akt, which in turn plays a central role during skeletal muscle regeneration. We show that mice with a skeletal muscle-restricted deletion of ILK develop a mild progressive muscular dystrophy mainly restricted to the MTJs with detachment of basement membranes and accumulation of extracellular matrix. Endurance exercise training enhances the defects at MTJs, leads to disturbed subsarcolemmal myofiber architecture, and abrogates phosphorylation of Ser473 as well as phosphorylation of Thr308 of PKB/Akt. The reduction in PKB/Akt activation is accompanied by an impaired insulin-like growth factor 1 receptor (IGF-1R) activation. Coimmunoprecipitation experiments reveal that the beta1 integrin subunit is associated with the IGF-1R in muscle cells. Our data identify the beta1 integrin-ILK complex as an important component of IGF-1R/insulin receptor substrate signaling to PKB/Akt during mechanical stress in skeletal muscle.

Sarcoplasmic Ca2+ release is prolonged in nonfailing myocardium of diabetic patients.

Background Asymptomatic diabetic patients have a high incidence of clinically unrecognized left ventricular dysfunction with an abnormal cardiac response to exercise. We, therefore, examined subclinical defects in the contraction-relaxation cycle and intracellular Ca(2+) regulation in myocardium of asymptomatic type 2 diabetic patients. Methods Alterations in the dynamics of the intracellular Ca(2+) transient and contractility were recorded in right atrial myocardium of type 2 diabetic patients and non-diabetic control tissue loaded with fura-2. In order to gain an insight into mechanisms underlying the altered Ca(2+) handling in diabetic myocardium levels of mRNA, protein expression and phosphorylation of key proteins in sarcoplasmic Ca(2+) handling were determined. Results In isolated atrial trabeculae of diabetic myocardium the rise of systolic Ca(2+) was significantly prolonged, but relaxation of the Ca(2+) transient was unaltered compared to control tissue. Accordingly, the levels of expression of mRNA and protein of the Ca(2+) release channel (RyR2) of the sarcoplasmic reticulum were reduced by 68 and 22%, respectively. Endogenous phosphorylation of RyR2 by protein kinases C, however, was increased by 31% in diabetic myocardium, as assessed by the back-phosphorylation technique. Levels of expression of SERCA2 and phospholamban were unaltered between both groups. Conclusions Intracellular Ca(2+) release is prolonged in non-failing myocardium of type 2 diabetic patients and this may be primarily due to a decreased expression of RyR2. This defective Ca(2+) release may represent an early stage of ventricular dysfunction in type 2 diabetes and would favor the abnormal response to exercise frequently observed in asymptomatic diabetic patients.

Extracorporeal circulation activates endothelial nitric oxide synthase in erythrocytes.

BACKGROUND: Extracorporeal circulation used in cardiopulmonary bypass and hemodialysis is often associated with severe hypotension, which is an important predictor for mortality and morbidity. One pathophysiological hypothesis includes nitric oxide (NO) generation. Recently, a functional NO synthase (endothelial type NO synthase [eNOS]), was found to be expressed in human red blood cells. However, to date, activation of red blood cell eNOS has not been shown. We hypothesized that eNOS in circulating red blood cells might be activated during extracorporeal circulation and thus contribute to hypotension through vasodilation upon NO release. METHODS: We collected blood samples from 28 patients electively subjected to cardiac surgery during cardiopulmonary bypass (0, 20, 40, 60, and 80 minutes of cardiopulmonary bypass; taken for routine blood gas analyses). Red blood cells were immunohistochemically stained against activated eNOS. The degree of activation was assessed by television densitometry (gray units). RESULTS: We found significant red blood cell eNOS activation during cardiopulmonary bypass in a time dependent fashion. The eNOS activation occurred by dissociation of the enzyme from the cellular membrane into the cytosol (translocation). The correlation between activated eNOS and bypass duration was highly significant. CONCLUSIONS: Red blood cells might contribute to hypotension through vasodilation upon NO release during extracorporeal circulation and could serve as new therapeutic targets in clinical practice.

Endothelial precursor cell migration during vasculogenesis.

Migration of endothelial precursor cells (so-called "angioblasts" in embryos and "endothelial progenitor cells" in adults) during vasculogenesis is a requirement for the formation of a primary vascular plexus. The migration is initiated by the change of endothelial precursors to their migratory phenotype. The endothelial precursor cells are then guided to the position where the primary vascular plexus is formed. Migration is stopped by the reversion of the cells to their nonmigratory phenotype. A combination of regulatory mechanisms and factors controls this process. These include gradients of soluble factors, extracellular matrix-cell interaction and cell-cell interaction. In this review, we give an overview of the regulation of angioblast migration during embryonic vasculogenesis and its relationship to the migration of endothelial progenitors during postnatal vascular development.

Mesenchymal stem cells induce endothelial activation via paracine mechanisms.

Mesenchymal stem cells (MSCs) are bone marrow-derived, pluripotent cells that possess the ability to transdifferentiate into various mesenchymal tissues such as bone, endothelium, and (heart) muscle. Therefore, these cells may provide a therapeutic tool, especially for the treatment of myocardial infarction. The interaction of the MSCs with the endothelial barrier and their ability to ultimately leave blood vessels after application are crucial in this context. In this study, the authors focused on the soluble factors produced by MSCs and their effect on the intracellular signal transduction of endothelial cells. The authors performed immunohistochemical measurements on human umbilical vein endothelial cells (HUVECs) treated with conditioned stem cell medium and took measurements of the intracellular nitric oxide (NO) levels and calcium changes. After application of conditioned stem cell medium, the authors detected an increase in endothelial NO synthase (eNOS) activity by translocation (Ca(2+)) and by phosphorylation (increase of pAKT and peNOS1177). Additionally, the authors observed an upregulation of pERK within the same time. The phosphorylated eNOS forms are linked to these findings and the increase of intracellular NO in the DAF measurements. Moreover, conditioned medium also increased intracellular calcium levels in endothelial cells. Concluding, the authors postulate that MSCs emit soluble factors that alter the NO and calcium levels of endothelial cells and may be important for facilitate crossing the endothelial barrier.

Effects of short-term vibration and hypoxia during high-intensity cycling exercise on circulating levels of angiogenic regulators in humans.

This study aimed to investigate the biological response to hypoxia as a stimulus, as well as exercise- and vibration-induced shear stress, which is known to induce angiogenesis. Twelve male cyclists (27.8 +/- 5.4 yr) participated in this study. Each subject completed four cycle training sessions under normal conditions (NC) without vibration, NC with vibration, normobaric hypoxic conditions (HC) without vibration, and HC with vibration. Each session lasted 90 min, and sessions were held at weekly intervals in a randomized order. Five blood samples (pretraining and 0 h post-, 0.5 h post-, 1 h post-, and 4 h posttraining) were taken from each subject at each training session. Hypoxia was induced by a normobaric hypoxic chamber with an altitude of 2,500 m. The mechanical forces (cycling with or without vibration) were induced by a cycling ergometer. The parameters VEGF, endostatin, and matrix metalloproteinases (MMPs) were analyzed using the ELISA method. VEGF showed a significant increase immediately after the exercise only with exogenously induced vibrations, as calculated with separate ANOVA analysis. Endostatin increased after training under all conditions. Western blot analysis was performed for the determination of endostatin corresponding to the 22-kDa cleavage product of collagen XVIII. This demonstrated elevated protein content for endostatin at 0 h postexercise. MMP-2 increased in three of the four training conditions. The exception was NC with vibration. MMP-9 reached its maximum level at 4 h postexercise. In conclusion, the results support the contention that mechanical stimuli differentially influence factors involved in the induction of angiogenesis. These findings may contribute to a broader understanding of angiogenesis.