Type 5 Adenylyl Cyclase Increases Oxidative Stress by Transcriptional Regulation of MnSOD via the SIRT1/FoxO3a Pathway
Background—For reasons that remain unclear, whether type 5 AC (AC5), one of two major AC isoforms in heart, is protective or deleterious in response to cardiac stress is controversial. To reconcile this controversy we examined the cardiomyopathy induced by chronic isoproterenol (ISO) in AC5 transgenic (Tg) mice and the signaling mechanisms involved.
Methods and Results—Chronic ISO increased oxidative stress and induced more severe cardiomyopathy in AC5 Tg, as left ventricular (LV) ejection fraction fell 1.9 fold more than wild type (WT), along with greater LV dilation and increased fibrosis, apoptosis and hypertrophy. Oxidative stress induced by chronic ISO, detected by 8-OhDG was 15% greater, p=0.007, in AC5 Tg hearts, while protein expression of MnSOD was reduced by 38%, indicating that the susceptibility of AC5 Tg to cardiomyopathy may be due to decreased MnSOD expression. Consistent with this, susceptibility of the AC5 Tg to cardiomyopathy was suppressed by overexpression of MnSOD, whereas protection afforded by the AC5 KO was lost in AC5 KO x MnSOD+/- mice. Elevation of MnSOD was eliminated by both sirtuin and MEK inhibitors, suggesting both the SIRT1/FoxO3a and MEK/ERK pathway are involved in MnSOD regulation by AC5.
Conclusions—Overexpression of AC5 exacerbates the cardiomyopathy induced by chronic catecholamine stress by altering regulation of SIRT1/FoxO3a, MEK/ERK and MnSOD, resulting in oxidative stress intolerance, thereby shedding light on new approaches for treatment of heart failure.
- Received January 8, 2013.
- Revision received March 12, 2013.
- Accepted March 14, 2013.