Cav3.2 T型鈣離子通道參與調控生理性心臟肥大

Abstract

T-型鈣離子通道(T-通道)只短暫表現在胚胎及幼體時期(Leuranguer et al., 2000; Niwa et al., 2004),並跟生長速率有緊密的關係(Xu and Best, 1992)。生長激素(Growth hormone)已知可透過IGF-1(Insulin-like growth hormone)的作用影響動物的體重和心臟的生長(Boguszewski et al., 1997; Ong et al., 2002; Xu and Best, 1991)。另外,IGF-1已被證實可以提高T-通道的電流強度(Piedras-Renteria et al., 1997)。目前發現在運動家生理性肥大心臟中有較多的IGF-1,故推測T-通道可能參與生理性心臟肥大的生成。為探討T-通道在運動引起的心臟肥大所扮演的角色,我們將野生型和CaV3.2型T-通道剔除的老鼠進行長達三週的游泳訓練,同時利用超音波觀察老鼠心臟的變化。在游泳前,野生型和CaV3.2-/-的左心室重量沒有明顯的差異。游泳三週後發現野生型老鼠的左心室明顯變重(0.11 ± 0.0028 (non-swim, n=7) 和0.13 ± 0.0029 (swim, n=7, p<0.001)。但是在CaV3.2-/-的左心室並沒有看到相同的變化(0.1099 ± 0.005 (non-swim, n=5) 和0.1036 ± 0.0028 (swim, n=5), p=0.3)。這個結果指出T-通道在生理性心臟肥大的形成是不可或缺的。

Voltage-gated T-type Ca2+ current (T-current) is temporarily recorded in cardiac myocytes during embryonic and postnatal period in some rodents (Leuranguer et al., 2000; Niwa et al., 2004) and was found linearly correlated with growth rate in rat of both sexes (Xu and Best, 1992). The growth of body weight and heart size has been well studied to be affected by chronically elevated growth hormone (GH) through the action of Insulin-like growth factor-1 (IGF-1) (Boguszewski et al., 1997; Ong et al., 2002; Xu and Best, 1991). Moreover, through the approach of patch-clamp, IGF-1 was found to be able to increase the current density of T-channels (Piedras-Renteria et al., 1997). Collectively, physiological cardiac hypertrophy in athletes is associated with increased cardiac IGF-1 formation, implying that T-channel might play a role in the physiological cardiac hypertrophy formation. To test the hypothesis that T-channels are involved in that cardiac remodeling during physiological cardiac hypertrophy, CaV3.2 T-type calcium channel deficient mice (CaV3.2-/-) were subjected to swimming training for 3 weeks and the development of cardiac hypertrophy was examined with echocardiography. At the basal level, there is no significant difference between wild type (WT) and CaV3.2-/- left ventricular mass (LVM) but after 3 weeks of swimming, WT showed a significant increase of LVM (0.11 ±0.0028 g (WT non-swim, n=7) and 0.13 ± 0.0029 g (WT swim, n=7, p<0.001). In contrast, swimming-induced physiological cardiac hypertrophy was blunted in CaV3.2-/-, the LVM were 0.1099 ± 0.005 (CaV3.2-/- non-swim, n=5) and 0.1036 ± 0.0028 (CaV3.2-/- swim 21ds, n=5, p=0.3). These findings suggest that CaV3.2 is necessary for triggering swimming-induced physiological cardiac hypertrophy.