Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Department of Anesthesiology, University of California San Diego, La Jolla, CA, 92093, USA.
Nat Commun. 2019 Aug 6;10(1):3533. doi: 10.1038/s41467-019-11389-1.
People heterozygous for an activating mutation in protein kinase G1 (PRKG1, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation. Prkg1 aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)-to increase wall stress in the ascending aorta-induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome.
携带蛋白激酶 G1（PRKG1，p.Arg177Gln）激活突变的杂合子个体在年轻时会发展为胸主动脉瘤和夹层（TAAD）。本文报道称，该突变的杂合子小鼠的基础蛋白激酶 G（PKG）活性增加了三倍，并出现了年龄依赖性的主动脉扩张。与野生型同窝仔鼠的主动脉相比，Prkg1 主动脉平滑肌细胞凋亡增加、弹性纤维断裂和氧化应激增加。经横向主动脉缩窄（TAC）处理以增加升主动脉壁的切向应力，可导致年轻突变小鼠发生严重的主动脉病变和主动脉破裂导致的死亡。自由基清除维生素 B 类似物 cobinamide 可完全预防与年龄相关的主动脉壁退行性变，而不相关的抗氧化剂 N-乙酰半胱氨酸可改善 TAC 诱导的病变。因此，基础 PKG 活性的增加会导致主动脉氧化应激，这引发了人们对广泛应用激活 PKG 药物治疗的担忧。cobinamide 可能成为治疗由氧化应激引起的主动脉瘤的一种方法，包括马凡综合征。
