Archiv für Kreislaufforschung

Heme oxygenase-1 (Hmox1) is a stress-inducible protein crucial in heme catabolism. The end products of its enzymatic activity possess anti-oxidative, anti-apoptotic and anti-inflammatory properties. Cardioprotective effects of Hmox1 were demonstrated in experimental models of myocardial infarction (MI). Nevertheless, its importance in timely resolution of post-ischemic inflammation remains incompletely understood. The aim of this study was to determine the role of Hmox1 in the monocyte/macrophage-mediated cardiac remodeling in a mouse model of MI. Hmox1 knockout (Hmox1−/−) and wild-type (WT, Hmox1+/+) mice were subjected to a permanent ligation of the left anterior descending coronary artery. Significantly lower incidence of left ventricle (LV) free wall rupture was noted between 3rd and 5th day after MI in Hmox1−/− mice resulting in their better overall survival. Then, starting from 7th until 21st day post-MI a more potent deterioration of LV function was observed in Hmox1−/− than in the surviving Hmox1+/+ mice. This was accompanied by higher numbers of Ly6Chi monocytes in peripheral blood, as well as higher expression of monocyte chemoattractant protein-1 and adhesion molecules in the hearts of MI-operated Hmox1−/− mice. Consequently, a greater post-MI monocyte-derived myocardial macrophage infiltration was noted in Hmox1-deficient individuals. Splenectomy decreased the numbers of circulating inflammatory Ly6Chi monocytes in blood, reduced the numbers of proinflammatory cardiac macrophages and significantly improved the post-MI LV function in Hmox1−/− mice. In conclusion, Hmox1 deficiency has divergent consequences in MI. On the one hand, it improves early post-MI survival by decreasing the occurrence of cardiac rupture. Afterwards, however, the hearts of Hmox1-deficient mice undergo adverse late LV remodeling due to overactive and prolonged post-ischemic inflammatory response. We identified spleen as an important source of these cardiovascular complications in Hmox1−/− mice.

This study was designed to evaluate whether the decreased early survival rate of diabetic rats submitted to acute experimental myocardial infarction can be improved by pretreatment with lidocaine. Male Wistar rats (±210g) were rendered diabetic with i.v. injection of streptozotocin (50 mg/kg), and only those presenting 1 week later a tail-blood glucose value between 250–400 mg/dl were retained in the protocol. Eleven weeks after induction of diabetes, a bolus of lidocaine (2mg/kg) was administered i.v. about 6 min prior to ligation of the left coronary artery under ether anesthesia in control (n=54) and diabetic (n=48) rats; similar studies were conducted in 53 control and 55 diabetic rats without lidocaine pretreatment. Adequate occlusion was confirmed by an elevation of plasma CK-MB levels 4h later or by a toluidine blue injection technique in rats which died earlier. Rats were followed over 48h and comparison in the survival rate in each group established with the Fisher's exact test. Early survival rate (measured after 20 min) was significantly decreased in diabetic rats (27% vs 45%; p=0.04). This was greatly improved by lidocaine pretreatment in diabetic (60% vs 27%; p=0.0013), but not in control animals (50% vs 45%; p=0.384). Furthermore, the beneficial effect of prophylactic lidocaine observed early after coronary ligation in diabetic rats was maintained throughout the period of observation (48h). These data suggest that the prophylactic use of lidocaine is able to reverse the increased incidence of sudden death following experimental myocardial infarction in chronically diabetic rats.

Sorcin is a 21.6–kDa Ca2+ binding protein of the penta–EF hand family. Several studies have shown that sorcin modulates multiple proteins involved in excitation–contraction (E–C) coupling in the heart, such as the cardiac ryanodine receptor (RyR2), L–type Ca2+ channel, and Na+–Ca2+ exchanger, while it has also been shown to be phosphorylated by cAMP–dependent protein kinase (PKA). To elucidate the effects of sorcin and its PKA–dependent regulation on E–C coupling in the heart, we identified the PKA–phosphorylation site of sorcin, and found that serine178 was preferentially phosphorylated by PKA and dephosphorylated by protein phosphatase– 1. Isoproterenol allowed sorcin to translocate to the sarcoplasmic reticulum (SR). In addition, adenovirus–mediated overexpression of sorcin in adult rat cardiomyocytes significantly increased both the rate of decay of the Ca2+ transient and the SR Ca2+ load. An assay of oxalate–facilitated Ca2+ uptake showed that recombinant sorcin increased Ca2+ uptake in a dose–dependent manner. These data suggest that sorcin activates the Ca2+–uptake function in the SR. In UM–X7. 1 cardiomyopathic hamster hearts, the relative amount of sorcin was significantly increased in the SR fraction, whereas it was significantly decreased in whole–heart homogenates. In failing hearts, PKA–phosphorylated sorcin was markedly increased, as assessed using a back–phosphorylation assay with immunoprecipitated sorcin. Our results suggest that sorcin activates Ca2+–ATPase–mediated Ca2+ uptake and restores SR Ca2+ content, and may play critical roles in compensatory mechanisms in both Ca2+ homeostasis and cardiac dysfunction in failing hearts.

Microvascular obstruction (MVO) and leakage (MVL) forms a pivotal part of microvascular damage following cardiac ischemia–reperfusion (IR). We tested the effect of relaxin therapy on MVO and MVL in mice following cardiac IR injury including severity of MVO and MVL, opening capillaries, infarct size, regional inflammation, cardiac function and remodelling, and permeability of cultured endothelial monolayer. Compared to vehicle group, relaxin treatment (50 μg/kg) reduced no-reflow area by 38% and the content of Evans blue as a permeability tracer by 56% in jeopardized myocardium (both P < 0.05), effects associated with increased opening capillaries. Relaxin also decreased leukocyte density, gene expression of cytokines, and mitigated IR-induced decrease in protein content of VE-cadherin and relaxin receptor. Infarct size was comparable between the two groups. At 2 weeks post-IR, relaxin treatment partially preserved cardiac contractile function and limited chamber dilatation versus untreated controls by echocardiography. Endothelial cell permeability assay demonstrated that relaxin attenuated leakage induced by hypoxia-reoxygenation, H2O2, or cytokines, action that was independent of nitric oxide but associated with the preservation of VE-cadherin. In conclusion, relaxin therapy attenuates IR-induced MVO and MVL and endothelial leakage. This protection was associated with reduced regional inflammatory responses and consequently led to alleviated adverse cardiac remodeling.

The contribution of vascular smooth muscle to the mechanical properties of arteries can be quantitated using elastomeric and classical muscle concepts. Such analyses can be performed using pressure-diameter data obtained from a given specimen under conditions of active and passive muscle. The elastomeric approach represents arterial wall mechanics in terms of incremental elastic moduli and theoretical characteristic impedance, Z0. Activation of muscle produces a reduction in values of incremental modulus at almost all values of transmural pressure. Values of Z0 are increased at low pressure and decreased at high pressure following activation of muscle. In the muscle approach, the mechanics of arteries are quantitated in terms of active stress development and constriction responses as a function of muscle length and pressure, respectively. Active stress-muscle lenght and shortening-load relations obtained from arterial smooth muscle are qualitatively similar to those of other types of muscles. The length and load dependencies of these relations are what one would expect based on a sliding filament arrangement of contractile filaments.

The importance of single components of ischemia including hypoxia, lactic acidosis, high potassium, and sympathetic stimulation to the spontaneous occurrence of ventricular arrhythmias was studied in chloralose-anesthetized cats using systemic and local intracoronary administration. Hypoxia and acidosis provoked no spontaneous arrhythmias regardless of systemic or regional administration. Systemic or local hyperpotassemia induced regularly ventricular ectopic activity including recurrent ventricular tachycardias that were characterized by a sudden onset and termination and by a stable rate. Stimulation of the left, right or bilateral stellate ganglia failed to provoke ventricular arrhythmias during hypoxia or acidosis and had also no influence on the initiation or rate of K+-induced ventricular tachycardias. The results indicate that high extracellular K+ may be the predominant arrhythmogenic factor of the components of ischemia we studied and that sympathetic ganglia stimulation does not affect K+-induced ventricular tachycardia.

The objective of the work was to examine whether adaptation to intermittent high altitude hypoxia and ischaemic preconditioning provide additive protection of the heart against subsequent acute ischaemic injury. Adult male rats were exposed to hypoxia (7000 m, 8 h/day, 24–30 exposures) in a hypobaric chamber. Susceptibility of their hearts to ischaemia-induced ventricular arrhythmias and infarction was evaluated in open-chest animals subjected to 30-min coronary artery occlusion and 4-h reperfusion. Preconditioning was induced by either two (PC1) or five (PC2) occlusions of the same artery for 5 min, each followed by 5-min reperfusion. Adaptation to hypoxia decreased the arrhythmia score from 2.75 ± 0.13 in normoxic controls to 2.17 ± 0.18. Both PC1 and PC2 reduced the arrhythmia score in the controls (0.15 ± 0.10 and 0.71 ± 0.24, respectively), as well as in the hypoxic groups (0.40 ± 0.15 and 0.27 ± 0.15, respectively). The infarct size was reduced from 66.6 ± 2.3% of the area at risk in the controls to 50.2 ± 1.9% in the adapted rats. PC1 conferred further protection in adapted animals (38.4 ± 2.8%) but this combined effect was of the same magnitude as that of preconditioning in the controls (37.5 ± 1.6%). Similar results were obtained using PC2. It is concluded that adaptation to hypoxia decreases the efficiency of ischaemic preconditioning; cardioprotective effects of these two phenomena are not additive. The results are consistent with the view that the mechanisms of protection conferred by chronic hypoxia and preconditioning may share the same signalling pathway.

Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease developing towards the end of pregnancy or in the months following delivery in previously healthy women in terms of cardiac disease. Enhanced oxidative stress and the subsequent cleavage of the nursing hormone Prolactin into an anti-angiogenic 16 kDa subfragment emerged as a potential causal factor of the disease. We established a prospective registry with confirmed PPCM present in 115 patients (mean baseline left ventricular ejection fraction, LVEF: 27 ± 9 %). Follow-up data (6 ± 3 months) showed LVEF improvement in 85 % and full recovery in 47 % while 15 % failed to recover with death in 2 % of patients. A positive family history of cardiomyopathy was present in 16.5 %. Pregnancy-associated hypertension was associated with a better outcome while a baseline LVEF ≤ 25 % was associated with a worse outcome. A high recovery rate (96 %) was observed in patients obtaining combination therapy with beta-blocker, angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor-blockers (ARBs) and bromocriptine. Increased serum levels of Cathepsin D, the enzyme that generates 16 kDa Prolactin, miR-146a, a direct target of 16 kDa Prolactin, N-terminal-pro-brain-natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) emerged as biomarkers for PPCM. In conclusion, low baseline LVEF is a predictor for poor outcome while pregnancy-induced hypertensive disorders are associated with a better outcome in this European PPCM cohort. The high recovery rate in this collective is associated with a treatment concept using beta-blockers, ACE inhibitors/ARBs and bromocriptine. Increased levels of Cathepsin D activity, miR-146a and ADMA in serum of PPCM patients support the pathophysiological role of 16 kDa Prolactin for PPCM and may be used as a specific diagnostic marker profile.

Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure.