Abstract 12893: Overexpression of Coupling Factor 6 Attenuates Physiological Cardiac Hypertrophy Induced by Swimming and Causes Systolic Cardiac Dysfunction in Mice
Background: Physiological cardiac hypertrophy (PCH) induced by regular exercise is usually beneficial. The activation of Akt was shown to be involved in PCH, but its regulatory mechanism is poorly understood. We recently reported that coupling factor 6 (CF6), an endogenous prostacyclin inhibitor, induces tissue acidosis by activating the acid-loading transporter ecto-F1Fo complex and causes systolic cardiac dysfunction. It was reported that cardiac tissue acidosis during ischemia impairs insulin-like growth factor (IGF)-1 signaling such as Akt. We tested the hypothesis that CF6 attenuates PCH induced by exercise and exacerbates systolic cardiac dysfunction in mice.
Methods and Results: Each of adult female wild type C57BL/6J mice (WT, n=10) and CF6-overexpressing transgenic mice (TG, n=16) were assigned to two groups, one of which was conditioned by swimming for 90 minutes twice daily for 4 weeks and the other was not (control). Baseline body weight, heart rate, arterial blood pressures, and echocardiographic findings with Philips HD11 XE with 15Hz linear probe were all similar among 4 groups. After 4-week swimming, body weight, heart rate, or arterial blood pressures did not differ among 4 groups. Left ventricular posterior wall (LVPW) and interventricular septum (IVS) thickness (cm) were increased by 0.012±0.01 and 0.016±0.01 respectively in WT (both p<0.01), but unchanged in TG. After 4-week swimming, LVPW and IVS were greater in WT than in TG (IVS, 0.88±0.01 in WT and 0.80±0.03 in TG, p= 0.027; LVPW, 0.88±0.02 in WT and 0.78±0.02 in TG, p<0.01). Fractional shortening (FS, %) was increased by swimming compared with control in WT (41±1 vs 37±1, p<0.01), whereas in TG, FS was similar between swimming and control mice (39±2 vs 39±1, p=ns). The expression of IGF-1 in the heart did not differ among 4 groups. The immunoreactive protein band for insulin receptor substrate-1 was decreased by 44±6% in TG by 4-week swimming (p<0.05) despite no change in WT. Phospho-Akt/Akt ratio was increased by 1.76±0.14 times in WT by 4-week swimming (p<0.05), whereas it was unchanged in TG.
Conclusions: Overexpression of CF6 attenuates exercise-induced PCH and causes systolic dysfunction by down-regulating insulin signaling and downstream component of Akt in mice.
- © 2010 by American Heart Association, Inc.