Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA.
Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Int J Mol Sci. 2019 Dec 27;21(1):203. doi: 10.3390/ijms21010203.
Humans with dilated cardiomyopathy (DCM) and heart failure (HF) develop low levels of corin, a multi-domain, cardiac-selective serine protease involved in natriuretic peptide cleavage and sodium and water regulation. However, experimental restoration of corin levels markedly attenuates HF progression. To determine whether the beneficial effects of corin in HF require catalytic activity, we engineered cardiac overexpression of an enzymatically inactive corin transgene (corin-Tg(i)). On a wild-type (WT) background, corin-Tg(i) had no evident phenotypic effects. However, in a well-established genetic model of DCM, corin-Tg(i)/DCM mice had increased survival ( < 0.01 to 0.001) vs. littermate corin-WT/DCM controls. Pleural effusion ( < 0.01), lung edema ( < 0.05), systemic extracellular free water ( < 0.01), and heart weight were decreased ( < 0.01) in corin-Tg(i)/DCM vs. corin-WT/DCM mice. Cardiac ejection fraction and fractional shortening improved ( < 0.01), while ventricular dilation decreased ( < 0.0001) in corin-Tg(i)/DCM mice. Plasma atrial natriuretic peptide, cyclic guanosine monophosphate, and neprilysin were significantly decreased. Cardiac phosphorylated glycogen synthase kinase-3β (pSer9-GSK3β) levels were increased in corin(i)-Tg/DCM mice ( < 0.01). In summary, catalytically inactive corin-Tg(i) decreased fluid retention, improved contractile function, decreased HF biomarkers, and diminished cardiac GSK3β activity. Thus, the protective effects of cardiac corin on HF progression and survival in experimental DCM do not require the serine protease activity of the molecule.
扩张型心肌病（DCM）和心力衰竭（HF）患者的心脏素水平降低，心脏素是一种多结构域、心脏选择性丝氨酸蛋白酶，参与利钠肽的切割以及钠和水的调节。然而，实验性恢复心脏素水平可显著减轻 HF 的进展。为了确定心脏素在 HF 中的有益作用是否需要催化活性，我们设计了一种酶失活的心脏素转基因（corin-Tg(i)）的心脏过表达。在野生型（WT）背景下，corin-Tg(i) 没有明显的表型效应。然而，在 DCM 的一种成熟的遗传模型中，corin-Tg(i)/DCM 小鼠的存活率增加（<0.01 至 0.001），与同窝对照的 corin-WT/DCM 相比。胸腔积液（<0.01）、肺水肿（<0.05）、全身细胞外游离水（<0.01）和心脏重量（<0.01）在 corin-Tg(i)/DCM 与 corin-WT/DCM 小鼠中降低。心脏射血分数和缩短分数改善（<0.01），而心室扩张减少（<0.0001），corin-Tg(i)/DCM 小鼠。血浆心钠素、环鸟苷单磷酸和 Neprilysin 显著降低。心脏磷酸化糖原合酶激酶-3β（pSer9-GSK3β）水平在 corin(i)-Tg/DCM 小鼠中升高（<0.01）。总之，酶失活的 corin-Tg(i) 减少了液体潴留，改善了收缩功能，降低了 HF 生物标志物，并减少了心脏 GSK3β 的活性。因此，心脏素对实验性 DCM 中 HF 进展和生存的保护作用不需要该分子的丝氨酸蛋白酶活性。
