Tufts Medical Center, Molecular Cardiology Research Institute, 800 Washington Street, Box 80, Boston, MA 02111.
J Gerontol A Biol Sci Med Sci. 2013 Nov;68(11):1351-5. doi: 10.1093/gerona/glt042. Epub 2013 May 8.
Hypertensive heart disease causes significant mortality in older patients, yet there is an incomplete understanding of molecular mechanisms that regulate age-dependent hypertensive left ventricular hypertrophy (LVH). Therefore, we tested the hypothesis that the cGMP-dependent protein kinase G I alpha (PKGIα) attenuates hypertensive LVH by evaluating the cardiac phenotype in mice with selective mutations of the PKGIα leucine zipper domain. These leucine zipper mutant (LZM) mice develop basal hypertension. Compared with wild-type controls, 8-month-old adult LZM mice developed increased left ventricular end-diastolic pressure but without frank LVH. In advanced age (15 months), the LZM mice developed overt pathological LVH. These findings reveal a role of PKGIα in normally attenuating hypertensive LVH. Therefore, mutation of the PKGIα LZ domain produces a clinically relevant model for hypertensive heart disease of aging.
高血压性心脏病会导致老年患者的死亡率显著上升，但对于调节年龄相关的高血压性左心室肥厚（LVH）的分子机制仍了解不完整。因此，我们通过评估选择性突变 PKGIα 亮氨酸拉链结构域的小鼠的心脏表型来检验假设，即 cGMP 依赖性蛋白激酶 G Iα（PKGIα）通过抑制高血压性 LVH 发挥作用。这些亮氨酸拉链突变（LZM）小鼠表现出基础高血压。与野生型对照组相比，8 月龄成年 LZM 小鼠的左心室舒张末期压升高，但没有明显的 LVH。在老年期（15 个月），LZM 小鼠出现明显的病理性 LVH。这些发现揭示了 PKGIα 在正常抑制高血压性 LVH 中的作用。因此，PKGIα LZ 结构域的突变产生了一种与年龄相关的高血压性心脏病的临床相关模型。
