Fig. 5

TAC-induced severe aortic pathology and death from aortic rupture in young Prkg1^RQ/+ mice. a Aortic arch by ultrasound imaging before and 2 weeks after TAC in a wild-type mouse (A = aortic root; B = ascending aorta; RPA=right pulmonary artery; LSA=left subclavian artery). b Survival of male wild type (WT, in blue) and PKG1^RQ/+ (RQ/+, in red) mice after TAC (n = 19 WT and n = 22 RQ/+). Some animals received N-acetylcysteine (NAC) for 4 weeks before and 2 weeks after TAC (n = 15 WT and n = 17 RQ/+). Only mice surviving 24 h after surgery were included, euthanized 14 days after surgery. **p < 0.01 by log-rank (Mantel–Cox) test for the indicated comparison. c Diameter of ascending aortas before and 14 days after TAC, measured in surviving WT and Prkg1^RQ/+ mice (n as in panel b, ***p < 0.001 by two-way ANOVA). d Media thickness measured on cross-sections of ascending aortas in surviving mice. e–g Elastin fiber breaks, SMC density, and apoptosis of media cells assessed on ascending aorta cross-sections of mice euthanized 14 days after TAC surgery (scale bars 25 μm; arrows show examples of elastin fiber breaks and TUNEL-positive nuclei). h DNA oxidation assessed by staining for 8-OH-deoxyguanosine in nuclei of media cells. i Media collagen content assessed on Masson–Trichrome stains. Boxplots in d–i show median and interquartile range with whiskers indicating the total range, for n = 6 male mice per group; *p < 0.05, **p < 0.01, ***p < 0.001 for the indicated comparisons by two-way ANOVA. Source data are provided as a Source Data file. j Schema summarizing consequences of mutant PKG1^RQ expression in the aorta. PKG1 activates JNK causing increased H₂O₂ production from NOX4 upregulation; oxidative stress further enhances JNK activation, activates and upregulates MMPs via JNK, and MMPs degrade elastin fibers. PKG1 activation causes SMC loss, in part via JNK activation and oxidative stress. PKG1 increases expression of contractile proteins, HIF-1α/VEGF, and TGF-β/TGF-β target genes; the latter promote aortic media fibrosis, which may be compensatory. Aortic media degeneration leads to age-dependent aortic dilation, and aortic dissections under hypertensive stress. Cobinamide (Cbi) or N-acetylcysteine (NAC) treatment reduce oxidative stress and JNK activation, preserving aortic media integrity