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.

The cardiac SR Ca(2+)-ATPase (SERCA2a) regulates intracellular Ca(2+)-handling and thus, plays a crucial role in initiating cardiac contraction and relaxation. SERCA2a may be modulated through its accessory phosphoprotein phospholamban or by direct phosphorylation through Ca(2+)/calmodulin dependent protein kinase II (CaMK II). As an inhibitory component phospholamban, in its dephosphorylated form, inhibits the Ca(2+)-dependent SERCA2a function, while protein kinase A dependent phosphorylation of the phospho-residues serine-16 or Ca(2+)/calmodulin-dependent phosphorylation of threonine-17 relieves this inhibition. Recent evidence suggests that direct phosphorylation at residue serine-38 in SERCA2a activates enzyme function and enhances Ca(2+)-reuptake into the sarcoplasmic reticulum (SR). These effects that are mediated through phosphorylation result in an overall increased SR Ca(2+)-load and enhanced contractility. In human heart failure patients, as well as animal models with induced heart failure, these modulations are altered and may result in an attenuated SR Ca(2+)-storage and modulated contractility. It is also believed that abnormalities in Ca(2+)-cycling are responsible for blunting the frequency potentiation of contractile force in the failing human heart. Advanced gene expression and modulatory approaches have focused on enhancing SERCA2a function via overexpressing SERCA2a under physiological and pathophysiological conditions to restore cardiac function, cardiac energetics and survival rate.

Background-Platelets from patients with type 2 diabetes mellitus display hyperaggregability and increased thrombogenic potential. Methods and Results-In platelets from patients with type 2 diabetes mellitus, we found enhanced tyrosine nitration and inactivation of the sarcoplasmic endoplasmic reticulum Ca 2ϩ -ATPase (SERCA-2), elevated platelet [Ca 2ϩ ] i , and activation of -calpain. The tyrosine nitration of SERCA-2 and the activation of -calpain in vitro in platelets from healthy volunteers could be evoked in vitro by peroxynitrite. Platelet endothelial cell adhesion molecule-1 was identified as a -calpain substrate; its in vitro degradation was stimulated by peroxynitrite and prevented by calpain inhibitors. Calpain activation also was linked to hyperresponsiveness to thrombin and the loss of platelet sensitivity to nitric oxide synthase inhibitors. Platelets from patients with type 2 diabetes mellitus (hemoglobin A 1c Ͼ6.6%) contained little or no intact platelet endothelial cell adhesion molecule-1, whereas degradation products were detectable. The peroxisome proliferator-activated receptor-␥ agonist rosiglitazone increased SERCA-2 expression in megakaryocytes, and treating patients with type 2 diabetes mellitus with rosiglitazone for 12 weeks increased platelet SERCA-2 expression and Ca 2ϩ -ATPase activity, decreased SERCA-2 tyrosine nitration, and normalized platelet [Ca 2ϩ ] i . Rosiglitazone also reduced -calpain activity, normalized platelet endothelial cell adhesion molecule-1 levels, and partially restored platelet sensitivity to nitric oxide synthase inhibition. Conclusion-These data identify megakaryocytes/platelets as additional cellular targets for peroxisome proliferator-activated receptor-␥ agonists and highlight potential benefits of rosiglitazone therapy in cardiovascular diseases.

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The present study investigated whether or not there may be differences in the direct cardiac actions of the novel, highly β1‐selective adrenoceptor antagonist nebivolol (NEB) in comparison to metoprolol (MET), bisoprolol (BIS), carvedilol (CAR) and bucindolol (BUC) in human myocardium (n=9). The rank order of β1‐selectivity as judged by competition experiments to 3H‐CGP 12.1777 in the presence of CGP 207.12 A (300 nmol l−1, Kiβ2) or ICI 118.551 (50 nmol l−1, Kiβ1) were NEB(Kiβ2/Kiβ1: 40.7)>BIS(15.6)>MET(4.23)>CAR(0.73)>BUC(0.49). The rank order of the negative inotropic potency of the β‐adrenoceptor antagonists measured in left ventricular trabeculae (dilated cardiomyopathy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (1 μmol l−1)‐stimulated force (IC50) was: MET (0.6 μmol l−1)>CAR (4.1 μmol l−1)>NEB (7.0 μmol l−1). NEB, BUC, MET and CAR did not not exert an intrinsic sympathomimetic activity (ISA) as determined by measurements of force development in forskolin (0.3 μmol l−1) pre‐treated left ventricular trabeculae, nor by measuring adenylate cyclase activity in forskolin (0.3 μmol l−1)‐stimulated assays (crude membranes). This also holds true for radioligand binding assays with or without guanine nucleotide guanyl‐5′‐yl imidodiphosphate (Gpp(NH)p). Although all studied β‐adrenoceptor antagonists lack intrinsic sympathomimetic activity (ISA), they differ in the β1‐selectivity as well as in their direct negative inotropic action. These differences as well as the mode of extracardiac action may have an impact on outcome of patients treated with β‐adrenoceptor antagonists. British Journal of Pharmacology (2001) 133, 1330–1338; doi: