The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca(2+)-independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload-induced cardiac dysfunction.