Department of Molecular, Cellular, and Developmental Biology and Biofrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
Cardiovasc Res. 2013 Dec 1;100(3):402-10. doi: 10.1093/cvr/cvt208. Epub 2013 Aug 28.
Calcium fluctuations and cardiac hypertrophy occur during pregnancy, but the role of the well-studied calcium-activated phosphatase, calcineurin, has not been studied in this setting. The purpose of this study was to determine whether calcineurin signalling is required for cardiac remodelling during pregnancy in mice.
We first examined calcineurin expression in the heart of mice during pregnancy. We found both calcineurin levels and activity were significantly increased in early-pregnancy and decreased in late-pregnancy. Since progesterone levels start to rise in early-pregnancy, we investigated whether progesterone alone was sufficient to modulate calcineurin levels in vivo. After implantation of progesterone pellets in non-pregnant female mice, cardiac mass increased, whereas cardiac function was maintained. In addition, calcineurin levels increased, which is also consistent with early-pregnancy. To determine whether these effects were occurring in the cardiac myocytes, we treated neonatal rat ventricular myocytes (NRVMs) with pregnancy-associated sex hormones. We found that progesterone treatment, but not oestradiol, increased calcineurin levels. To obtain a functional read-out of increased calcineurin activity, we measured the activity of the transcription factor NFAT, a downstream target of calcineurin. Progesterone treatment significantly increased NFAT activity in NRVMs, and this was blocked by the calcineurin inhibitor cyclosporine A (CsA), showing that the progesterone-mediated increase in NFAT activity requires calcineurin activity. Importantly, CsA treatment of mice completely blocked pregnancy-induced cardiac hypertrophy.
Our results show that calcineurin is required for pregnancy-induced cardiac hypertrophy, and that calcineurin activity in early-pregnancy is due at least in part to increased progesterone.
钙波动和心脏肥大发生在怀孕期间，但钙激活磷酸酶，钙调神经磷酸酶，在这种情况下的作用尚未被研究。本研究的目的是确定钙调神经磷酸酶信号是否需要在小鼠怀孕期间进行心脏重塑。
我们首先检查了怀孕小鼠心脏中的钙调神经磷酸酶表达。我们发现钙调神经磷酸酶水平和活性在早孕时显着增加，在孕晚期降低。由于孕激素水平在早孕时开始上升，我们研究了孕激素是否单独足以调节体内钙调神经磷酸酶水平。在非怀孕雌性小鼠植入孕激素丸后，心脏质量增加，而心脏功能得以维持。此外，钙调神经磷酸酶水平增加，这也与早孕时一致。为了确定这些影响是否发生在心肌细胞中，我们用妊娠相关性激素处理新生大鼠心室肌细胞（NRVM）。我们发现孕激素治疗，但不是雌二醇，增加了钙调神经磷酸酶水平。为了获得钙调神经磷酸酶活性增加的功能读数，我们测量了转录因子 NFAT 的活性，钙调神经磷酸酶的下游靶标。孕激素处理显着增加了 NRVM 中的 NFAT 活性，并且这被钙调神经磷酸酶抑制剂环孢素 A（CsA）阻断，表明孕激素介导的 NFAT 活性增加需要钙调神经磷酸酶活性。重要的是，CsA 处理的小鼠完全阻断了妊娠引起的心脏肥大。
我们的结果表明，钙调神经磷酸酶是妊娠引起的心脏肥大所必需的，并且早孕时钙调神经磷酸酶的活性至少部分归因于孕激素的增加。
