Stretch activates jun N-terminal kinase/stress-activated protein kinase in vascular smooth muscle cells through mechanisms involving autocrine ATP stimulation of purinoceptors
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作者:
Hamada, K
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机构:Univ Tokyo, Fac Med, Dept Physiol, Bunkyo Ku, Tokyo 113, Japan
Hamada, K
Takuwa, N
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机构:Univ Tokyo, Fac Med, Dept Physiol, Bunkyo Ku, Tokyo 113, Japan
Takuwa, N
Yokoyama, K
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机构:Univ Tokyo, Fac Med, Dept Physiol, Bunkyo Ku, Tokyo 113, Japan
Yokoyama, K
Takuwa, Y
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机构:Univ Tokyo, Fac Med, Dept Physiol, Bunkyo Ku, Tokyo 113, Japan
Takuwa, Y
机构:
[1] Univ Tokyo, Fac Med, Dept Physiol, Bunkyo Ku, Tokyo 113, Japan
[2] Univ Tokyo, Fac Med, Dept Cardiovasc Biol, Bunkyo Ku, Tokyo 113, Japan
[3] RIKEN Tsukuba Life Sci Ctr, Ibaraki, Osaka 305, Japan
Mechanical strain has been implicated in phenotypic changes, including alteration of gene expression in vascular smooth muscle cells; however, the molecular basis for mechanotransduction leading to nuclear gene expression is largely unknown. We demonstrate in the present study that cyclic stretching of vascular smooth muscle cells dramatically activates Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) through an autocrine mechanism. Stretch causes time- and strength-dependent rise of the ATP concentration in media. The stretch-induced activation JNK/SAPK is attenuated by the addition of hexokinase or apyrase that scavenge ATP in media. Both the P-2 receptor antagonist and the A(1) subtype selective P-1 receptor antagonist partially inhibit stretch-induced activation of JNK/SAPK, The conditioned medium from stretched cells contains an activity to stimulate JNK/SAPK. The JNK-stimulating activity in the conditioned medium from stretched cells is attenuated by the addition of apyrase or P-1 and P-2 receptor antagonists. The addition of exog enous ATP or adenosine induces dose-dependent activation of JNK/SAPK. These results indicate that stretch activates JNK/SAPK in vascular smooth muscle cells through mechanisms involving autocrine stimulation of purinoceptors by ATP and its hydrolyzed product adenosine.