Gradual cold acclimation induces cardioprotection without affecting ß-adrenergic receptor-mediated adenylyl cyclase signaling.

Novel strategies are needed that can stimulate endogenous signaling pathways to protect the heart from myocardial infarction. The present study tested the hypothesis that appropriate regimen of cold acclimation (CA) may provide a promising approach for improving myocardial resistance to ischemia/reperfusion (I/R) injury without negative side effects. We evaluated myocardial I/R injury, mitochondrial swelling, and ß-adrenergic receptor (ß-AR)-adenylyl cyclase-mediated signaling. Male Wistar rats were exposed to CA (8°C, 8 h/day for a week, followed by 4 wk at 8°C for 24 h/day), while the recovery group (CAR) was kept at 24°C for an additional 2 wk. The myocardial infarction induced by coronary occlusion for 20 min followed by 3-h reperfusion was reduced from 56% in controls to 30% and 23% after CA and CAR, respectively. In line, the rate of mitochondrial swelling at 200 µM Ca2+ was decreased in both groups. Acute administration of metoprolol decreased infarction in control group and did not affect the CA-elicited cardiprotection. Accordingly, neither ß1-AR-Gsα-adenylyl cyclase signaling, stimulated with specific ligands, nor p-PKA/PKA ratios were affected after CA or CAR. Importantly, Western blot and immunofluorescence analyses revealed ß2- and ß3-AR protein enrichment in membranes in both experimental groups. We conclude that gradual cold acclimation results in a persisting increase of myocardial resistance to I/R injury without hypertension and hypertrophy. The cardioprotective phenotype is associated with unaltered adenylyl cyclase signaling and increased mitochondrial resistance to Ca2+-overload. The potential role of upregulated ß2/ß3-AR pathways remains to be elucidated.NEW & NOTEWORTHY We present a new model of mild gradual cold acclimation increasing tolerance to myocardial ischemia/reperfusion injury without hypertension and hypertrophy. Cardioprotective phenotype is accompanied by unaltered adenylyl cyclase signaling and increased mitochondrial resistance to Ca2+-overload. The potential role of upregulated ß2/ß3-adrenoreceptor activation is considered. These findings may stimulate the development of novel preventive and therapeutic strategies against myocardial ischemia/reperfusion injury.

Beneficial effect of continuous normobaric hypoxia on ventricular dilatation in rats with post-infarction heart failure.

Adaptation to continuous normobaric hypoxia (CNH) protects the heart against ischemia/reperfusion injury but much less is known about its potential therapeutic effects. The aim of this study was to find out whether post-infarction exposure to CNH can attenuate the progression of heart failure. Ten-week-old male rats underwent myocardial infarction (MI) or sham operation. MI was induced by 60-min coronary artery occlusion. Seven days post-MI, the rats were randomly assigned to two groups: i) sedentary controls kept at room air and ii) rats exposed to CNH (12 % O(2), 3 weeks). Echocardiographic examination of the left ventricle (LV) was performed 3 days before surgery and 7, 14 and 28 days post-MI. MI resulted in a gradual increase in LV end-diastolic diameter (LVD(d)) compared to sham-operated animals. Fractional shortening (FS) decreased from 42.8 % before MI to 15.1 % on day 28 post-MI. CNH significantly attenuated ventricular dilatation without affecting scar area and FS. Our data suggest that prolonged exposure to CNH has certain potential to attenuate the progression of unfavorable changes in ventricular geometry induced by MI in rats.

Role of NO/cGMP signaling pathway in cardiac ischemic tolerance of chronically hypoxic rats.

It has been suggested that increase in acute nitric oxide (NO) or cyclic guanosine monophosphate production may be involved in cardioprotection induced by chronic hypoxia (CH). We studied the effect of NO donor molsidomine and phosphodiesterase type 5 inhibitor sildenafil on myocardial ischemia/reperfusion (I/R) injury in rats adapted to CH. Male Wistar rats were exposed to continuous hypoxia in a normobaric chamber (10 % O(2), 4 weeks). Rats received either saline, molsidomine (10 mg/kg body weight, i.v.) or sildenafil (0.7 mg/kg body weight, i.v.) 30 min before ischemia. Control rats were kept under normoxia and treated in a corresponding manner. Adaptation to CH increased the myocardial ischemic tolerance. Acute treatment with either molsidomine or sildenafil significantly reduced infarct size in normoxic rats and further enhanced cardioprotection induced by CH. However, the cardioprotective effect of CH on I/R injury was not additive to the cardioprotection provided by the drugs.

Tumour necrosis factor-α contributes to improved cardiac ischaemic tolerance in rats adapted to chronic continuous hypoxia.

AIM: It has been demonstrated that tumour necrosis factor-alpha (TNF-α) via its receptor 2 (TNFR2) plays a role in the cardioprotective effects of preconditioning. It is also well known that chronic hypoxia is associated with activation of inflammatory response. With this background, we hypothesized that TNF-α signalling may contribute to the improved ischaemic tolerance of chronically hypoxic hearts. METHODS: Adult male Wistar rats were kept either at room air (normoxic controls) or at continuous normobaric hypoxia (CNH; inspired O2 fraction 0.1) for 3 weeks; subgroups of animals were treated with infliximab (monoclonal antibody against TNF-α; 5 mg kg(-1), i.p., once a week). Myocardial levels of oxidative stress markers and the expression of selected signalling molecules were analysed. Infarct size (tetrazolium staining) was assessed in open-chest rats subjected to acute coronary artery occlusion/reperfusion. RESULTS: CNH increased myocardial TNF-α level and expression of TNFR2; this response was abolished by infliximab treatment. CNH reduced myocardial infarct size from 50.8 ± 4.3% of the area at risk in normoxic animals to 35.5 ± 2.4%. Infliximab abolished the protective effect of CNH (44.9 ± 2.0%). CNH increased the levels of oxidative stress markers (3-nitrotyrosine and malondialdehyde), the expression of nuclear factor κB and manganese superoxide dismutase, while these effects were absent in infliximab-treated animals. CNH-elevated levels of inducible nitric oxide synthase and cyclooxygenase 2 were not affected by infliximab. CONCLUSION: TNF-α plays a role in the induction of ischaemia-resistant cardiac phenotype of CNH rats, possibly via the activation of protective redox signalling.