Abstract P305: Detrimental Effects of Chronic Activation of AKT in Hearts from Ozone-Exposed Healthy Adult Rats
Death of cardiomyocytes results in decreased cardiac function, which correlates with overall morbidity and mortality in many different clinical settings. For these reasons, understanding the intracellular signaling pathways that control cardiomyocyte survival has significant clinical implications. Each year in the US 60,000 cardiovascular deaths have been linked to environmental pollutants such as ozone (O3). Earlier studies from our laboratory have shown that myocardial dysfunction, subsequent to chronic O3 exposure, in normal adult rats. This attenuation of cardiac function was associated with increased myocardial TNF-alpha (TNF-α) levels. Progressive increases in the expression of myocardial TNF-α in 4 and 8 week O3 exposed animals were followed by decreases in cardiac caveolin-1 levels. Acute activation of the serine-threonine kinase Akt is cardioprotective and reduces both infarction and dysfunction after ischemia/reperfusion injury (IRI). Akt is activated in samples from patients with chronic heart failure, however, less is known about the chronic effects of Akt activation in the hearts from ozone exposed patients. Although caveolin-1 has been shown to negatively regulate AKT expression; a cell survival pathway, regulatory role of AKT in hearts from ozone exposed subjects has never been studied. Sprague Dawley rats were exposed 8 hr/day for 28 and 56 days to filtered air or 0.8 ppm O3. In order to assess the chronic effects to O3, expressions of AKT and p-AKT were determined by wetern blotting in hearts extracted from rats, 24 hr after termination of air or O3 exposure. Compared to rats exposed to filtered air, total AKT levels were significantly increased in all O3 exposed animals. Similar results were seen with pAKT levels. Since earlier studies have determined detrimental effects of chronic activation of AKT in ischemia reperfusion injury, our novel findings suggest the interesting possibility of a mechanism by which chronic Akt activation can become maladaptive after exposure to chronic levels of ozone. It is possible that PI3K-dependent but Akt-independent effectors are required for full cardioprotection. Studies are currently in progress to prove this hypothesis and complete study will be presented at the meeting in New Orleans in 2011.
- © 2011 by American Heart Association, Inc.