Abstract 1277: Nectin-2 is Required to Prevent Cardiac Fibrosis and Dysfunction in Response to Chronic Pressure Overload
Background The intercalated disc transduces mechanical and electrical signaling to adjoining cardiac myocytes, and changes in its architecture have been considered to be involved in cardiac dysfunction. Nectins are Ca2+-independent immunoglobulin-like cell-cell adhesion molecules which associate with cadherins to form adherens junctions, and are linked to the actin cytoskeleton by interaction with the F actin-binding protein afadin. Nectin-2 is expressed in various tissues, and, among isoforms of nectin, it is selectively expressed at intercalated discs in the heart. However, little is known about the role of nectin-2 in the heart.
Methods and Results Nectin-2 knockout (KO) mice, which were kindly provided by Dr. E. Wimmer at State University of New York, showed normal cardiac structure and function in physiological conditions. To investigate the role of nectin-2 in pathological conditions, we performed ascending aortic banding in 11 week-old male mice. Four weeks after banding, both nectin-2 KO and wild-type mice developed similar degrees of cardiac hypertrophy as evaluated by heart weight/body weight ratio and the cross sectional area of cardiac myocyte (% control; 142.2 ± 16.9 % in nectin-2 KO vs. 143.9 ± 9.1 % in wild-type, p=ns.). However, cardiac function assessed by echocardiography was significantly impaired in nectin-2 KO mice compared with wild-type mice (% FS; 36.8 ± 3.1 % in nectin-2 KO vs. 44.4 ± 2.0 % in wild-type, p0.05), which was associated with the increases of lung weight/body weight ratio and cardiac fibrosis (% section; 21.7 ± 2.5 % in nectin-2 KO vs. 4.8 ± 0.8 % in wild-type, p<0.001). Electron microscopy revealed the destruction of the intercalated discs accompanied by disorganized myofibrils in nectin-2 KO mice even 2 weeks after banding. Phosphorylated p38MAPK and ERK in the hearts of sham-operated nectin-2 KO mice increased compared with those of sham-operated wild-type mice, while their increasing responses against pressure overload were markedly impaired in nectin-2 KO mice.
Conclusion These results indicate that nectin-2 maintains the molecular mechanisms linking the cytoskeleton to intracellular signaling pathways and prevents cardiac fibrosis and dysfunction in response to chronic pressure overload.