The effect of type II diabetes and the metabolic syndrome on cardiac second window of preconditioning

Preconditioning is the most powerful endogenous mechanism, to protect the heart against ischemic damage. Conflicting data are published whether preconditioning can be induced in case of diabetes and the metabolic syndrome, which are clinically very relevant conditions. If preconditioning could be induced consistently and chronically in this population, an important reduction of surgical morbidity and mortality could be reached. In this project we induced hypoxic preconditioning in mice and used cardiac pressure-conductance catheterisation and infarct size as outcome parameters. In the first part, we found that hypoxic preconditioning was capable to reduce infarct size with 40% and preserve the load-independent parameters with 33% after coronary occlusion. A DKO (double knock-out: ob/ob; LDLR-/-) model for the metabolic syndrome developed a larger infarct size and had a reduced contractility. No preconditioning could be induced in this model. To detect the determing factor of the resistance to preconditioning, we used single knock-out models. A comparable preconditioning effect of wild type mice could be induced in the lipoprotein receptor deficient (LDLR-/-) model for dyslipidemia. The leptin deficient (ob/ob) model, characterized by insulin resistance and abdominal obesity had, identically to the DKO model, a larger infarct size. A second window of preconditioning could be induced, although it was less pronounced than the wild type and LDLR-/- model. Insulin resistance and abdominal obesity could be identified as the major factor in the resistance to preconditioning.status: publishe

ACE-inhibition, but not weight reduction restores cardiomyocyte response to β-adrenergic stimulation in the metabolic syndrome

Diabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is additionally increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. A first aim was to study cardiomyocyte contractility and Ca2+ handling in vitro in a mouse model of MS. A second aim was to investigate whether in vivo hypocaloric diet or ACE-inhibition (ACE-I) improved cardiomyocyte contractility in vitro, contractile reserve and Ca2+ handling.status: publishe

Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice

Hypertension is an underlying risk factor for cardiovascular disease. Despite this, its pathogenesis remains unknown in most cases. Recently, the transient receptor potential (TRP) channel family was associated with the development of several cardiovascular diseases linked to hypertension. The melastatin TRP channels TRPM4 and TRPM5 have distinct properties within the TRP channel family: they form nonselective cation channels activated by intracellular calcium ions. Here we report the identification of TRPM4 proteins in endothelial cells, heart, kidney, and chromaffin cells from the adrenal gland, suggesting that they have a role in the cardiovascular system. Consistent with this hypothesis, Trpm4 gene deletion in mice altered long-term regulation of blood pressure toward hypertensive levels. No changes in locomotor activity, renin-angiotensin system function, electrolyte and fluid balance, vascular contractility, and cardiac contractility under basal conditions were observed. By contrast, inhibition of ganglionic transmission with either hexamethonium or prazosin abolished the difference in blood pressure between Trpm4–/– and wild-type mice. Strikingly, plasma epinephrine concentration as well as urinary excretion of catecholamine metabolites were substantially elevated in Trpm4–/– mice. In freshly isolated chromaffin cells, lack of TRPM4 was shown to cause markedly more acetylcholine-induced exocytotic release events, while neither cytosolic calcium concentration, size, nor density of vesicles were different. We therefore conclude that TRPM4 proteins limit catecholamine release from chromaffin cells and that this contributes to increased sympathetic tone and hypertension