Doctor of Philosophy in Regulatory Biology, Cleveland State University, 2007, College of Science

Background: This project examined JAK-STAT pathway activation in two mouse models of cardiac hypertrophy: autoimmune myocarditis and pressure overload (PO). Methods: Myocarditis was induced with cardiac myosin; PO was induced by transverse aortic constriction. STAT1, 3, and 5 binding was assessed by gel shift. STATs, JAKs, SERCA2A, and calsequestrin (CSQ) were quantified. In myocarditis, P-STAT3 localization to cardiac myocyte nuclei was ascertained, and plasma IL-6 and ventricular ANF mRNA were analyzed. Results: In myocarditis, STAT3/3 and STAT1/1 activation, inflammation, increased ventricle weight (P < 0.0001), and ANF mRNA (P = 0.005) occurred on days 14, 21, and 28. In PO, activation appeared on day 7 and persisted to failure. P-STAT3 increased (myocarditis, P < 0.0001; pressure overload, P < 0.05). P-JAK1 increased in myocarditis on days 21 and 28 (P < 0.007). In PO, CSQ and SERCA2A levels did not differ, but in myocarditis CSQ decreased (P = 0.02). In myocarditis, a biphasic elevation in plasma IL-6 occurred (P = 0.003). Conclusions: Although JAK-STAT signaling is activated in both models, it occurs earlier in PO and persists to heart failure, whereas in myocarditis it declines to basal levels as inflammation and plasma IL-6 return to baseline.

Committee: Christine Moravec (Advisor) Subjects: