Adiponectin Protects Rat Myocardium Against Chronic Intermittent Hypoxia-induced Injury

Objectives:Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular diseases such as heart failure, hypertension, atherosclerosis, and arrhythmia and so on. Of the many associated factors, chronic intermittent hypoxia (CIH) in particular is the primary player in OSAS. To investigate the effects of the Adiponectin (Ad) on rat myocardium injury induced by chronic intermittent hypoxia (CIH).Methods:To assess the effects of CIH on cardiac function secondary to OSAS, we established a model to study the effects of CIH on Wistar rats. Specifically, we examined the possible underlying cellular mechanisms of hypoxic tissue damage and the possible protective role of adiponectin against hypoxic insults. In the first treatment group, rats were exposed to CIH conditions (nadir O2,5-6%) for 8 hours/day, for 5 weeks. Subsequent CIH-induced cardiac dysfunction was measured by echocardiograph. Terminal deoxynucleotidyl transfer-mediated dUTP nick end-labeling (TUNEL) analysis was used to detect the myocardial apoptosis. masson analysis was used to detect the left ventricular fibrosis and western blot was used to assess the protein expression of endoplasmic reticulum stress, AMPK pathway, collagen Ⅰ, collagen Ⅲ and TGF-β/smad2/3 pathway. Gene analysis by RT-PCR was used to investigate the CHOP, GRP78, MMP2 and TIMP2.Results:Compared with the normal control (NC) group, rats in the CIH-exposed group experienced elevated levels of left ventricular end-systolic dimension and left ventricular end-systolic volume and depressed levels of left ventricular ejection fraction and left ventricular fractional shortening (p< 0.05). However, when adiponectin (Ad) was added in CIH+Ad group, we saw a rescue in the elevations of the aforementioned left ventricular function (p< 0.05). TUNEL showed that the apoptosis percentage in CIH group (2.948%) was significantly higher than that in NC group (0.4167%) and CIH+ Ad group (1.219%) (p< 0.05). Protein expressions of cleaved caspase-3, cleaved caspase-9, and cleaved-caspase-12 validated our TUNEL results (p< 0.05). Mechanistically, our results demonstrated that the proteins expressed with endoplasmic reticulum stress and the expression of reactive oxygen species (ROS) were significantly elevated under CIH conditions, whereas Ad supplementation partially decreased them. The fibrosis of left ventricular in CIH group was significantly severer than that in NC group and CIH+Ad group (P<0.05), although there was still statistical difference between the two groups (P<0.05). In addition, the protein expression of collagen I and collagen III were the highest in CIH group but the lowest in NC group, with CIH+ Ad group in between. There was a significant difference among three groups (all P< 0.05). The TGF-β/smad2/3 pathway was significantly activated in CIH group, but less activated in CIH+Ad group (P<0.05).Conclusions:Overall, our results suggested that Ad augmentation could improve CIH-induced left ventricular dysfunction by inhibition of myocardial apoptosis and left ventricular remodeling.