Pressure overload induces greater hypertrophy and mortality in female mice with p38α MAPK inhibition

We examined pressure overload left ventricular (LV) hypertrophy (H) induced by aortic banding in transgenic mice with cardiac-specific expression of a dominant negative (DN) p38 alpha (TG) and wild type controls (WT). In response to chronic pressure overload, induced by aortic constriction, LV/BW increased more, p < 0.05, in female TG (6.4 +/- 0.2, n = 7) than in WT female (5.1 +/- 0.2, n = 10), or male TG or WT (5.0 +/- 0.2, n = 10 vs. 5.5 +/- 0.2, n = 8). Lung/BW, an index of LV decompensation, was significantly higher, p < 0.05, in banded female TG (14 +/- 1.2 mg/g) than in WT females (9.0 +/- 0.8), or male TG or WT (8.2 +/- 0.7 vs. 9.3 +/- 1.3). This was associated with higher premature mortality, p < 0.05, in banded female TG mice (42%) compared with banded WT females (10%), TG mates (13%), or WT males (17%). In male, but not female, TG mice, the number of TUNEL-positive cells was smaller, p < 0.05, compared with WT. Phospho-Akt kinase activity increased (p < 0.05) in female TG after banding, but not in males. After ovariectomy, chronic pressure overload no longer induced greater mortality, greater LVH, or p-Akt levels in female TG mice, and like male TG mice, apoptosis was protected. DN-p38 alpha enhanced estrogen-induced activation of Akt in cultured cardiac myocytes. Thus, inhibition of p38 alpha MAPK paradoxically augments LVH resulting in cardiac decompensation and increased mortality in response to pressure overload more in female mice than male mice, which could be due to increased Akt activation and/or through cross-talk between p38 alpha MAPK and Akt. (c) 2006 Elsevier Inc. All rights reserved.