Gradual cold acclimation induces cardioprotection without affecting adrenergic beta-receptor-mediated adenylyl cyclase signaling
Abstract
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 (UR) injury without negative side effects.
We evaluated myocardial UR injury, mitochondrial swelling, and beta-adrenergic receptor (beta-AR)-adenylyl cyclase-mediated signaling. Male Wistar rats were exposed to CA (8 degrees C, 8 h/day for a week, followed by 4 wk at 8 degrees C for 24 h/day), while the recovery group (CAR) was kept at 24 degrees 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 mu M 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 beta 1-AR-G(s)alpha-adenyly-1- cyclase signaling. stimulated with specific ligands, nor p-PKA/PICA ratios were affected after CA or CAR.
Importantly. Western blot and immunofluorescence analyses revealed beta 2- and beta 3-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 beta 2/beta 3-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 beta 2/beta 3-adrenoreceptor activation is considered.
These findings may stimulate the development of novel preventive and therapeutic strategies against myocardial ischemia/reperfusion injury.