To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, ...its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research.
Die Universität ist die größte Forschungs- und Bildungsorganisation unserer Gesellschaft und bildet dennoch einen weißen Fleck in der öffentlichen Wahrnehmung. Als Wissenschaftler und ehemaliger ...Universitätspräsident macht Hans Michael Piper deshalb die Innenwelt dieser Institution verständlich: Er erklärt, warum Studierende in ihrer Studienzeit eine entscheidende gesellschaftliche Prägung erfahren, warum Professor*innen egoistisch sein müssen oder warum hundert Gremien der Freiheit von Lehre und Forschung dienen - und was diese Freiheit gefährdet. Seine persönlichen Erfahrungen machen die Komplexität des deutschen Hochschulsystems sichtbar und verdeutlichen die Bedeutung der Universität als Bildungseinrichtung.
Peroxisome proliferator‐activated receptors (PPARα, ‐β and ‐γ) are nuclear receptors involved in transcriptional regulation of lipid and energy metabolism. Since the energy demand increases when ...cardiac progenitor cells are developing rhythmic contractile activity, PPAR activation may play a critical role during cardiomyogenesis of embryonic stem (ES) cells. It is shown that ES cells express PPARα, ‐β, and ‐γ mRNA during differentiation of ES cells towards cardiac cells. Treatment with PPARα agonists (WY14643, GW7647, and ciprofibrate) significantly increased cardiomyogenesis and expression of the cardiac genes MLC2a, ANP, MHC‐β, MLC2v, and cardiac α‐actin. Furthermore, WY14643 increased PPARα gene expression and the expression of the cardiogenic transcription factors GATA‐4, Nkx2.5, DTEF‐1, and MEF 2C. In contrast, the PPARα antagonist MK886 decreased cardiomyogenesis, whereas the PPARβ agonist L‐165,041 as well as the PPARγ agonist GW1929 were without effects. Treatment with PPARα, but not PPARβ, and PPARγ agonists and MK886, resulted in generation of reactive oxygen species (ROS), which was inhibited in the presence of the NADPH oxidase inhibitors diphenylen iodonium (DPI) and apocynin and the free radical scavengers vitamin E and N‐(2‐mercapto‐propionyl)‐glycine (NMPG), whereas the mitochondrial complex I inhibitor rotenone was without effects. The effect of PPARα agonists on cardiomyogenesis of ES cells was abolished upon preincubation with free radical scavengers and NADPH oxidase inhibitors, indicating involvement of ROS in PPARα, mediated cardiac differentiation. In summary, our data indicate that stimulation of PPARα but not PPARβ and ‐γ enhances cardiomyogenesis in ES cells using a pathway that involves ROS and NADPH oxidase activity.
Disclosure of potential conflicts of interest is found at the end of this article.
Reperfusion may induce additional cell death in patients with acute myocardial infarction receiving primary angioplasty or thrombolysis. Altered intracellular Ca(2+) handling was initially considered ...an essential mechanism of reperfusion-induced cardiomyocyte death. However, more recent studies have demonstrated the importance of Ca(2+)-independent mechanisms that converge on mitochondrial permeability transition (MPT) and are shared by cardiomyocytes and other cell types. This article analyses the importance of Ca(2+)-dependent cell death in light of these new observations. Altered Ca(2+) handling includes increased cytosolic Ca(2+) levels, leading to activation of calpain-mediated proteolysis and sarcoplasmic reticulum-driven oscillations; this can induce hypercontracture, but also MPT due to the privileged Ca(2+) transfer between sarcoplasmic reticulum and mitochondria through cytosolic Ca(2+) microdomains. In the opposite direction, permeability transition can worsen altered Ca(2+) handling and favour hypercontracture. Ca(2+) appears to play an important role in cell death during the initial minutes of reperfusion, particularly after brief periods of ischaemia. Developing effective and safe treatments to prevent Ca(2+)-mediated cardiomyocyte death in patients with transient ischaemia, by targeting Ca(2+) influx, intracellular Ca(2+) handling, or Ca(2+)-induced cell death effectors, is an unmet challenge with important therapeutic implications and large potential clinical impact.
OBJECTIVE—Insulin is a key regulator of metabolism, but it also confers protective effects on the cardiovascular system. Here, we analyze the mechanism by which insulin stabilizes endothelial barrier ...function.
METHODS AND RESULTS—Insulin reduced basal and antagonized tumor necrosis factor-α-induced macromolecule permeability of rat coronary microvascular endothelial monolayers. It also abolished reperfusion-induced vascular leakage in isolated-perfused rat hearts. Insulin induced dephosphorylation of the regulatory myosin light chains, as well as translocation of actin and vascular endothelial (VE)-cadherin to cell borders, indicating a reduction in contractile activation and stabilization of cell adhesion structures. These protective effects were blocked by genistein or Hydroxy-2-naphthalenylmethylphosphonic acid tris acetoxymethyl ester (HNMPA-AM3), a pan-tyrosine-kinase or specific insulin-receptor-kinase inhibitor, respectively. Insulin stimulated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and NO production, and it activated Rac1. Inhibition of PI3K/Akt abrogated Rac1 activation and insulin-induced barrier protection, whereas inhibition of the endothelial nitric oxide synthase/soluble guanylyl cyclase pathway partially inhibited them. Inhibition of Rac1 abrogated the assembly of actin at cell borders. Accordingly, it abolished the protective effect of insulin on barrier function of the cultured endothelial monolayer, as well as the intact coronary system of ischemic-reperfused hearts.
CONCLUSION—Insulin stabilizes endothelial barrier via inactivation of the endothelial contractile machinery and enhancement of cell-cell adhesions. These effects are mediated via PI3K/Akt- and NO/cGMP-induced Rac1 activation.
Cardiovascular cells (cardiomyocytes and smooth muscle cells) are target cells for parathyroid hormone (PTH) and the structurally related peptide parathyroid hormone-related peptide (PTH-rP). PTH ...activates protein kinase C (PKC) of cardiomyocytes via a PKC activating domain previously identified on chondrocytes. Activation of PKC leads to hypertrophic growth and re-expression of fetal type proteins in cardiomyocytes. This hypertrophic effect of PTH might contribute to left ventricular hypertrophy in hemodialysis patients with secondary hyperparathyroidism. PTH-rP is expressed in cardiovascular cells (endothelial cells and smooth muscle cells). It does not mimic the above described actions of PTH but exerts effects of its own on cardiomyocytes. These effects involve activation of protein kinase A, via a N-terminal domain distinct from that identified on PTH, and activation of PKC, via a C-terminally located domain distinct from that found on PTH. On smooth muscle cells PTH and PTH-rP reduce the influence of extracellular calcium, through cAMP-dependent mechanisms. These inhibitory effects on voltage-dependent L-type calcium channels of smooth muscle cells cause vasorelaxation. Present studies concerning cardiovascular actions of either PTH and PTH-rP suggest that increased plasma levels of PTH and PTH-rP influence cardiomyocyte and smooth muscle cell physiology. It can be assumed that PTH-rP acts as a paracrine or autocrine modulator in heart and vessels.
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