Rothermel B A, McKinsey T A, Vega R B, Nicol R L, Mammen P, Yang J, Antos C L, Shelton J M, Bassel-Duby R, Olson E N, Williams R S
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3328-33. doi: 10.1073/pnas.041614798.
Signaling events controlled by calcineurin promote cardiac hypertrophy, but the degree to which such pathways are required to transduce the effects of various hypertrophic stimuli remains uncertain. In particular, the administration of immunosuppressive drugs that inhibit calcineurin has inconsistent effects in blocking cardiac hypertrophy in various animal models. As an alternative approach to inhibiting calcineurin in the hearts of intact animals, transgenic mice were engineered to overexpress a human cDNA encoding the calcineurin-binding protein, myocyte-enriched calcineurin-interacting protein-1 (hMCIP1) under control of the cardiac-specific, alpha-myosin heavy chain promoter (alpha-MHC). In unstressed mice, forced expression of hMCIP1 resulted in a 5-10% decline in cardiac mass relative to wild-type littermates, but otherwise produced no apparent structural or functional abnormalities. However, cardiac-specific expression of hMCIP1 inhibited cardiac hypertrophy, reinduction of fetal gene expression, and progression to dilated cardiomyopathy that otherwise result from expression of a constitutively active form of calcineurin. Expression of the hMCIP1 transgene also inhibited hypertrophic responses to beta-adrenergic receptor stimulation or exercise training. These results demonstrate that levels of hMCIP1 producing no apparent deleterious effects in cells of the normal heart are sufficient to inhibit several forms of cardiac hypertrophy, and suggest an important role for calcineurin signaling in diverse forms of cardiac hypertrophy. The future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure.
由钙调神经磷酸酶控制的信号转导事件会促进心肌肥大，但这些途径在转导各种肥大刺激的作用中所需的程度仍不确定。特别是，在各种动物模型中，给予抑制钙调神经磷酸酶的免疫抑制药物在阻断心肌肥大方面具有不一致的效果。作为在完整动物心脏中抑制钙调神经磷酸酶的另一种方法，构建了转基因小鼠，使其在心脏特异性的α-肌球蛋白重链启动子（α-MHC）的控制下过表达编码钙调神经磷酸酶结合蛋白——富含心肌细胞的钙调神经磷酸酶相互作用蛋白-1（hMCIP1）的人cDNA。在未受应激的小鼠中，hMCIP1的强制表达导致心脏重量相对于野生型同窝小鼠下降5%-10%，但除此之外未产生明显的结构或功能异常。然而，hMCIP1的心脏特异性表达抑制了心肌肥大、胎儿基因表达的重新诱导以及向扩张型心肌病的进展，而这些情况在其他情况下是由组成型活性形式的钙调神经磷酸酶的表达所导致的。hMCIP1转基因的表达还抑制了对β-肾上腺素能受体刺激或运动训练的肥大反应。这些结果表明，在正常心脏细胞中不产生明显有害影响的hMCIP1水平足以抑制多种形式的心肌肥大，并提示钙调神经磷酸酶信号在多种形式的心肌肥大中起重要作用。未来开发在心脏内选择性增加MCIP蛋白表达或活性的措施可能对预防心力衰竭具有临床价值。
