Background and Aims: Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive. Methods: Ascending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a β-aminopropionitrile monofumarate–induced AD model. Results: The transcriptional profiles of 93 397 cells revealed a dynamic temporal-specific phenotypic transition and marked elevation of the activator protein-1 (AP-1) complex, actively enabling synthetic SMC expansion. Mechanistically, tumour necrosis factor signalling enhanced AP-1 transcriptional activity by dampening mitochondrial oxidative phosphorylation (OXPHOS). Targeting this axis with the OXPHOS enhancer coenzyme Q10 or AP-1-specific inhibitor T-5224 impedes phenotypic transition and aortic degeneration while improving survival by 42.88% (58.3%–83.3% for coenzyme Q10 treatment), 150.15% (33.3%–83.3% for 2-week T-5224), and 175.38% (33.3%–91.7% for 3-week T-5224) in the β-aminopropionitrile monofumarate–induced AD model. Conclusions: This cross-sectional compendium of cellular atlas of human ascending aortas during AD progression provides previously unappreciated insights into a transcriptional programme permitting aortic degeneration, highlighting a translational proof of concept for an anti-remodelling intervention as an attractive strategy to manage temporal-specific AD by modulating the tumour necrosis factor–OXPHOS–AP-1 axis.

Medial degeneration and inflammation are features of abdominal aortic aneurysms (AAAs). However, the early inflammatory event initiating aneurysm formation remains to be identified. Activated platelets release abundant proinflammatory cytokines and are involved in initial inflammation in various vascular diseases. We investigated the role of platelets in progression of AAA in vivo and in vitro. Histological studies of tissues of patients with AAA revealed that the number of platelets was increased in aneurysm sites along with the increased infiltration of T lymphocytes and augmented angiogenesis. In a murine model of AAA, apolipoprotein E-knockout mice infused with 1,000 ng/kg/min angiotensin II, treatment with clopidogrel, an inhibitor of platelets, significantly suppressed aneurysm formation (47% decrease, P<0.05). The clopidogrel also suppressed changes in aortic expansion, elastic lamina degradation and inflammatory cytokine expression. Moreover, the infiltration of macrophages and production of matrix metalloproteinases (MMPs) were also significantly reduced by clopidogrel treatment. In vitro incubation of macrophages with isolated platelets stimulated MMP activity by 45%. These results demonstrate a critical role for platelets in vascular inflammation and AAA progression.

Thoracic aortic surgery and cardiopulmonary bypass are both associated with development of postoperative acute kidney injury. In this study, we undertook to investigate the relationship between cardiopulmonary bypass time and postoperative acute kidney injury in patients undergoing thoracic aortic surgery for acute DeBakey Type I aortic dissection. All patients receiving thoracic aortic surgery for acute DeBakey Type I aortic dissection in Beijing Anzhen hospital from December 2015 to April 2017 were included. Cardiopulmonary bypass time was recorded during surgery. Acute kidney injury was defined based on the Kidney Disease Improving Global Outcomes criteria. A total of 115 consecutive patients were eventually analyzed. The overall incidence of acute kidney injury was 53.0% (n = 61). The average age was 47.8 ± 10.7 years; 74.8% were male. Mean cardiopulmonary bypass time was 211 ± 56 min. In-hospital mortality was 7.8%. Multivariate logistic regression revealed that cardiopulmonary bypass time was independently associated with the occurrence of postoperative acute kidney injury after adjust confounding factors (odds ratio = 1.171; 95% confidence interval: 1.002–1.368; P = 0.047). Cardiopulmonary bypass time is independently associated with an increased hazard of acute kidney injury after thoracic aortic surgery for acute DeBakey Type I aortic dissection. Further understanding of the mechanism of this association is crucial to the design of preventative strategies.

Rationale: Genetic editing has shown great potential for the treatment of human hereditary disorders via the elimination of mutations in embryos. However, the efficiency and safety of germline gene editing are not well understood. Objective: We aimed to examine the preclinical efficacy/safety of embryonic base editing in a mouse model of hypertrophic cardiomyopathy (HCM) using a novel adenine base editor (ABE) platform. Methods and Results: Here, we described the use of an ABEmax-NG to directly correct the pathogenic R404Q/+ mutation ( Myh6 c.1211C>T) in embryos for a mouse model of HCM, increasing the number of wild-type embryos for in vitro fertilization. Delivery of the ABEmax-NG mRNA to embryos from R404Q/+ HCM mice resulted in 62.5% to 70.8% correction of the Myh6 c.1211C>T, reducing the level of mutant RNA and eliminating HCM in the postnatal mice as well as their offspring. In addition, the same single guide RNA was also used to target an intronic locus (chr2: +36,585,842) with an overall editing rate of 86.7%, thus confirming that ABEmax-NG can efficiently edit target loci with different protospacer adjacent motifs (PAM) and genomic distribution in vivo. Compared with CRISPR/single-stranded oligodeoxynucleotides–mediated correction, ABEmax-NG displayed a much higher correction rate without introducing indels. DNA and RNA off-target analysis did not detect off-target editing in treated embryos and founder mice. In utero injection of adeno-associated virus 9 encoding the ABEmax-NG also resulted in around 25.3% correction of the pathogenic mutation and reduced of mutant RNA, thereby indicating ABEmax-NG has the potential to correct the HCM mutation in vivo. Conclusions: We developed an ABEmax-NG system, which efficiently corrected a pathogenic Myh6 HCM mutation in mouse embryos without off-target lesions, thus safely eliminating HCM in derived mice and their progeny.