Abstract 1830: Protein Quality Control Inadequacy Activates NFAT Signaling in Cardiomyocytes
Protein Quality Control (PQC) assists proper (re)folding of nascent polypeptides, keeps normal mature proteins from denaturing or misfolding, and timely removes terminally misfolded and irreparable damaged proteins in the cell. PQC is enforced by collaboration between chaperones and targeted proteolysis. The latter is primarily mediated by the ubiquitin-proteasome system (UPS) while a large family of chaperones are heat shock proteins (HSPs), including small HSPs. αB-crystallin (CryAB) is the most abundant small HSP in cardiomyocytes. Signs of severe PQC inadequacy, including abnormal protein aggregation, reduced CryAB protein, and functional insufficiency of the proteasome, were all observed in failing human hearts, supporting a novel hypothesis that PQC inadequacy contributes to the genesis of congestive heart failure (CHF). It is well established that the calcineurin-NFAT pathway regulates the expression of a significant subset of genes associated with cardiac remodeling and failure. We present here several lines of new genetic and pharmacological evidence that PQC inadequacy suffices to activate NFAT signaling in both cultured neonatal rat cardiomyocytes (NRCMs) and intact mouse hearts. NFAT translocation from cytoplasm to the nucleus is critical to its activation. We observed in cultured NRCMs that CryAB overexpression (o/e) significantly reduced adrenergic agonists-induced NFAT nuclear translocation and myocyte hypertrophy while pharmacological inhibition of the proteasome induced significant calcineurin-dependent NFAT nuclear translocation. Using a NFAT-luciferase reporter mouse model, we detected that NFAT transactivation was increased by a factor of 3 in a mouse cardiomyopathy model that was created by transgenic o/e of a misfolded desmin protein and displayed severe PQC inadequacy. Similarly, we found that NFAT activities in the heart of CryAB/HSPB2 null mice were significantly increased. Consistently, these mice developed cardiac hypertrophy and malfunction at the baseline and displayed exacerbated cardiac hypertrophy and malfunction upon transverse aortic constriction (TAC). Finally, cardiac-specific CryAB o/e significantly attenuated NFAT activation and cardiac hypertrophic responses induced by TAC.
This research has received full or partial funding support from the American Heart Association, AHA National Center.