| Alpha B-crystallin (CryAB) is the most abundant small heat shock protein (HSP) constitutively expressed in heart muscle cells. Similar to most of the other HSPs, CryAB is also inducible in the heart by stress conditions such as hemodynamic overload and ischemia/reperfusion injury. In end-stage failing human hearts, however, CryAB expression at both transcript and protein levels is significantly down-regulated. Gain- and loss-of-function studies have consistently demonstrated a protective role of CryAB on myocardial ischemia/reperfusion injury. However, the role(s) of HSPs in cardiac response to mechanical overload is unknown.; This study was designed to explore the potentially beneficial role(s) of CryAB in the cardiac responses to hypertrophic stress. Transgenic (TG) mice with cardiac-specific overexpression of the CryAB gene, non-transgenic (NTG) mice, and CryAB/HSPB2 double knockout (KO) mice underwent either transverse aortic constriction (TAC) surgery to induce left ventricular pressure overload, or sham surgery for control. Cardiac responses were analyzed at 2- and 10-weeks post-TAC using left ventricular catheterization, gravimetry, fetal gene expression profiling, and isolated myocyte morphometry.; Two weeks after left ventricular pressure overload, TG mouse hearts showed attenuated cardiac hypertrophy compared to NTG mice. This was evident at the hypertrophic gene transcription level as well as in the gross morphology, suggesting that induction of cardiac hypertrophy in the presence of CryAB overexpression was less pathological. On the contrary, the absence of CryAB/HSPB2 had profound effects on the molecular, cellular and whole organ level cardiac remodeling. KO mice showed rapid development of cardiac hypertrophy and progression to congestive cardiac failure, compared to NTG TAC mice. Interestingly, an abnormal cardiac phenotype was also observed in the KO sham mice. These results suggest that CryAB and/or HSPB2 are essential for normal cellular function and absence of these HSPs has detrimental effects on the heart, especially during pressure overload. In vitro tests suggest that the beneficial effects of CryAB may be attributable to attenuation of NFAT signaling.; It is concluded that CryAB/HSPB2 modulates the cardiac response to mechanical overload. |
