Role of ErbB (EGFR) tyrosine kinase receptors in adult and aging heart
Aging is considered as a major risk factor for heart failure. Multiple factors are involved in aging-related cardiac dysfunction. The epidermal growth factor (EGF) signaling pathway is one of those implicated to be important in aging-related cardiac and neural dysfunction and invasiveness of breast carcinoma. Blockade of signaling of ErbB-2/ErbB-4 tyrosine kinase receptors or the ligand, heparin-binding EGF leads to cardiac dysfunction. ErbB-1 may protect the heart against stress-induced injury and its ligand, EGF increases myocardial contractility. However, the role of ErbB-1 receptors in adult and aging heart is not clear. The goal of this thesis was to investigate ErbB-1 signaling in the aging heart and its contribution in the maintenance of adult cardiac function. We found that ErbB expression in aging mouse hearts was attenuated at transcriptional, translational and post-translational levels accompanied by decreased cardiac function. Using the ecdysone-inducible gene expression system, we expressed dominant-negative ErbB-1 mutant receptors (hErbB-1-mut) that block endogenous cardiac ErbB-1 signaling specifically in cardiomyocytes of young adult mice. hErbB-1-mut expression led to blockade of endogenous ErbB-1/ErbB-2 phosphorylation. Increase in left ventricular (LV) mass, atrial natriuretic factor expression and histological changes were indicative of cardiac hypertrophy as seen in the aged mice. Cardiac dilation, numerous cardiac lesions and loss of clear boundary between cardiac fibrils were noted histologically. Early and long-term hErbB-1-mut induction led to a significant decrease in fractional shortening, and a significant increase in LV end-systolic diameter as seen in aged mice and this was reversed by discontinuation of the inducer. Survival rate of transverse-aortic constricted hErbB-1-mut mice was significantly reduced. Dobutamine stimulation led to blunted inotropic responses while adenylyl cyclase stimulation normalized the depressed cardiac function. Collectively, these observations indicate that attenuation of cardiac ErbB-1 signaling leads to cardiac dysfunction as seen in aged hearts. Conversely, ErbB-1 is important for the maintenance of normal adult cardiac function and this regulatory role may be compromised in aging myocardium leading to abnormal cardiac function seen in the aged population.