Abstract 173: TNNI3K, a Cardiac-Specific Kinase, Promotes Cardiac Hypertrophy in vivo
Background:TNNI3K is a novel cardiac specific mitogen-activated protein kinase (MAPK), and directly interacts with cardiac troponin I. Although the members of the MAPK cascade have been implicated as important regulators of cardiac hypertrophy, the effects of TNNI3K in heart are unknown.
Methods and results: To determine whether TNNI3K is involved in pressure-overload-induced cardiac hypertrophy, TNNI3K expression was examined by real-time PCR analysis in left ventricular samples of rats obtained at various times after transverse aortic constriction (TAC). A dramatic decrease was observed in TNNI3K expression (0.66%) on the day 1, followed by a slowly continuously increase up to 14 days (1.62-fold) after TAC. To investigate the role of TNNI3K in cardiac hypertrophy, we generated three lines of transgenic mice with cardiac-restricted overexpression of TNNI3K, which carry 1, 5, and 15 copies of the transgene, respectively. Concentric cardiac hypertrophy was detected in all TNNI3K transgenic mice lines, and the degree of hypertrophy is correlated with the transgenic integration numbers. In comparison with non-transgenic littermates, the ratio of heart/body weight was significantly increased of 16% at 10 weeks of age in the TNNI3K transgenic mice with high copy number (P<0.05). The left ventricular thickness was dramatically increased (45% and 45% increase in IVSd and LVPWd, respectively, P<0.01, P<0.01) and the left ventricular chamber dimension was significantly decreased (24% and 32% decrease in LVEDD and LVESD, respectively, P<0.01, P<0.05) in high-copy-number TNNI3K transgenic mice, as measured by echocardiography. Both left ventricular systolic pressures (+34%, P<0.05) and left ventricular function (dP/dtmax) (+12%) were higher in high-copy-number TNNI3K transgenic mice as measured by closed-chest catheter. The TNNI3K transgenic mice had normal cytoarchitecture without fibrosis at 10 weeks of age. No signs of cardiomyopathy or lethality were detected up to 12 months.
Conclusion: Our results indicate that TNNI3K is involved in pressure-overload induced cardiac hypertrophy. The cardiac-restricted overexpression of TNNI3K promotes cardiac hypertrophy with augmented cardiac function.