Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Howard Hughes Medical Institute, Children's Hospital Medical Center, Cincinnati, Ohio, USA.
J Clin Invest. 2009 Dec;119(12):3787-96. doi: 10.1172/JCI39724. Epub 2009 Nov 16.
In noncontractile cells, increases in intracellular Ca2+ concentration serve as a second messenger to signal proliferation, differentiation, metabolism, motility, and cell death. Many of these Ca2+-dependent regulatory processes operate in cardiomyocytes, although it remains unclear how Ca2+ serves as a second messenger given the high Ca2+ concentrations that control contraction. T-type Ca2+ channels are reexpressed in adult ventricular myocytes during pathologic hypertrophy, although their physiologic function remains unknown. Here we generated cardiac-specific transgenic mice with inducible expression of alpha1G, which generates Cav3.1 current, to investigate whether this type of Ca2+ influx mechanism regulates the cardiac hypertrophic response. Unexpectedly, alpha1G transgenic mice showed no cardiac pathology despite large increases in Ca2+ influx, and they were even partially resistant to pressure overload-, isoproterenol-, and exercise-induced cardiac hypertrophy. Conversely, alpha1G-/- mice displayed enhanced hypertrophic responses following pressure overload or isoproterenol infusion. Enhanced hypertrophy and disease in alpha1G-/- mice was rescued with the alpha1G transgene, demonstrating a myocyte-autonomous requirement of alpha1G for protection. Mechanistically, alpha1G interacted with NOS3, which augmented cGMP-dependent protein kinase type I activity in alpha1G transgenic hearts after pressure overload. Further, the anti-hypertrophic effect of alpha1G overexpression was abrogated by a NOS3 inhibitor and by crossing the mice onto the Nos3-/- background. Thus, cardiac alpha1G reexpression and its associated pool of T-type Ca2+ antagonize cardiac hypertrophy through a NOS3-dependent signaling mechanism.
在非收缩细胞中，细胞内 Ca2+浓度的增加作为第二信使，信号传递增殖、分化、代谢、运动和细胞死亡。尽管不清楚 Ca2+如何作为第二信使，因为控制收缩的 Ca2+浓度很高，但这些 Ca2+依赖性调节过程中的许多都在心肌细胞中起作用。T 型 Ca2+通道在病理性肥大的成年心室肌细胞中重新表达，尽管其生理功能仍不清楚。在这里，我们生成了心脏特异性转基因小鼠，可诱导表达生成 Cav3.1 电流的 alpha1G，以研究这种类型的 Ca2+内流机制是否调节心脏肥厚反应。出乎意料的是，尽管 Ca2+内流大量增加，但 alpha1G 转基因小鼠没有出现心脏病理学，它们甚至对压力超负荷、异丙肾上腺素和运动引起的心脏肥厚有部分抗性。相反，alpha1G-/- 小鼠在压力超负荷或异丙肾上腺素输注后表现出增强的肥厚反应。alpha1G-/- 小鼠的增强型肥厚和疾病通过 alpha1G 转基因得到挽救，表明 alpha1G 在心肌细胞中对保护有自主需求。在机制上，alpha1G 与 NOS3 相互作用，NOS3 在压力超负荷后增加 alpha1G 转基因心脏中的 cGMP 依赖性蛋白激酶 I 活性。此外，NOS3 抑制剂和将小鼠交叉到 Nos3-/- 背景上可以消除 alpha1G 过表达的抗肥厚作用。因此，心脏 alpha1G 再表达及其相关的 T 型 Ca2+库通过 NOS3 依赖性信号机制拮抗心脏肥厚。
