Abstract 9028: Endogenous Digitalis-Like Compounds May Regulate Cardiac Hypertrophy/Failure
We showed before that in isolated cardiac myocytes, digitalis binding to NaK- ATPase α1 isoform initiates selective activation of the class 1A PI3K/Akt signaling pathways, causing myocyte hypertrophy akin to physiological growth. This suggests that putative endogenous digitalis-like compounds (EDLs) may have beneficial effects on cardiac function and growth, including the ability to antagonize pressure overload-induced hypertrophy. To test this hypothesis, it was necessary to use a transgenic mouse, because the natural rodent NaK-ATPase α1 (in contrast to that of man) is highly insensitive to digitalis, and not likely to respond to physiological levels of EDLs. Hence we generated a NaK-ATPase α1-sensitive mouse (α1 S/S) by amino acid substitutions, leaving the other Na,K-ATPase isoforms in their natural states. This transgenic mouse and the Wt control (α1R/R) were then subjected to transverse aortic constriction (TAC) or sham operation, and compared. There were no differences in body weight, organ (heart, lung, kidney and liver) weight and systolic blood pressure (tail cuff) between α1R/R and α1 S/S at the age of 12 weeks. Echocardiography showed that basal relative left ventricular wall thickness (LVWT) in α1 S/S was increased compared to that in α1R/R. In α1 S/S subjected to TAC, LVWT continued to increase during 4 weeks after surgery; FS and EF were increased, and no enlargement in chamber sizes was observed at 4 weeks after TAC. In α1R/R subjected to TAC, the peak increase in LVWT was 2 weeks after surgery; at 4 weeks after TAC, an enlargement in end systolic dimension of LV was observed, and cardiac functions showed a downward trend. TAC-induced cardiac hypertrophy was attenuated significantly in α1 S/S compared to α1R/R in the postmortem analysis. In α1R/R, HW/BW and LVW/BW were increased, 4 weeks after TAC, by 53.2%; and 47.9%;, respectively (n=5 per group). However, in α1 S/S, HW/BW and LVW/BW were increased, 4 weeks after TAC, by 21.3%; and 21.0%;, respectively (n=7 per group). These results are consistent with the existence of EDLs whose levels are high enough in α1 S/S mice to activate NaK-ATPase/ class 1A PI3K/Akt pathways, and partially overcome the TAC-induced activation of class 1B PI3K and the resulting maladaptive hypertrophy.
- © 2010 by American Heart Association, Inc.