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Supplemental Digital Content is available in the text. Background: Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the MLX gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients. MLX single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX. Methods: To elucidate the hypothesis that the single-nucleotide polymorphism of the MLX gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses. Results: We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that MLX mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage–endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK. Conclusions: MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation. [ABSTRACT FROM AUTHOR]

Aging is a critical risk factor for heart disease, including ischemic heart disease and heart failure. Cellular senescence, characterized by DNA damage, resistance to apoptosis and the senescence-associated secretory phenotype (SASP), occurs in many cell types, including cardiomyocytes. Senescence precipitates the aging process in surrounding cells and the organ through paracrine mechanisms. Generalized autophagy, which degrades cytosolic materials in a non-selective manner, is decreased during aging in the heart. This decrease causes deterioration of cellular quality control mechanisms, facilitates aging and negatively affects lifespan in animals, including mice. Although suppression of generalized autophagy could promote senescence, it remains unclear whether the suppression of autophagy directly stimulates senescence in cardiomyocytes, which, in turn, promotes myocardial dysfunction in the heart. We addressed this question using mouse models with a loss of autophagy function. Suppression of general autophagy in cardiac-specific Atg7 knockout ( Atg7 cKO) mice caused accumulation of senescent cardiomyocytes. Induction of senescence via downregulation of Atg7 was also observed in chimeric Atg7 cardiac-specific KO mice and cultured cardiomyocytes in vitro , suggesting that the effect of autophagy suppression upon induction of senescence is cell autonomous. ABT-263, a senolytic agent, reduced the number of senescent myocytes and improved cardiac function in Atg7 cKO mice. Suppression of autophagy and induction of senescence were also observed in doxorubicin-treated hearts, where activation of autophagy alleviated senescence in cardiomyocytes and cardiac dysfunction. These results suggest that suppression of general autophagy directly induces senescence in cardiomyocytes, which in turn promotes cardiac dysfunction.

Competing Interests: DECLARATIONS Conflicts of interest Both authors declared that there are no conflicts of interest.

Background: This study aimed to investigate the effect of periodontal disease (PD) on the outcomes of patients with coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI)., Methods and results: The study included 77 consecutive non-smoking patients with de novo coronary lesions treated with a drug-eluting stent (DES). Periodontal measurements, including the community periodontal index (CPI), were performed by independent periodontists. A CPI score of ≥3 was used to define PD. The occurrence of major adverse cardiac events (MACEs), which were defined as a composite of cardiovascular death, non-fatal myocardial infarction, target lesion revascularization, or non-target lesion revascularization, was compared between patients with and without PD. Of the 77 patients, 49 (63.6%) exhibited a CPI score of 3 or 4 and were assigned to the PD group. The remaining 28 patients (36.4%) were assigned to the non-PD group. Baseline clinical characteristics and angiographic findings were comparable between the 2 groups. MACEs occurred in 13 (26.5%) of the PD patients and 2 (7.1%) of the non-PD patients. Kaplan-Meier analysis showed a significantly lower MACE-free survival rate in the PD group than for the non-PD group (P=0.034)., Conclusions: PD at baseline was associated with an increased risk of MACEs in CAD patients who were treated with a DES for de novo coronary lesions.