key: cord-0022586-dzt6bc18
authors: Zhang, Shumin; Liu, Zhujiang; Xie, Nan; Huang, Chuanbo; Li, Zhiqing; Yu, Fang; Fu, Yi; Cui, Qinghua; Kong, Wei
title: Pan-HDAC (Histone Deacetylase) Inhibitors Increase Susceptibility of Thoracic Aortic Aneurysm and Dissection in Mice
date: 2021-09-16
journal: Arterioscler Thromb Vasc Biol
DOI: 10.1161/atvbaha.121.316808
sha: 52d3a8612b7547015aa6a80613c1cc3f48441808
doc_id: 22586
cord_uid: dzt6bc18

nan

T horacic aortic aneurysm and dissection (TAAD) is a highly lethal aortic disease. Administration of a lysyl oxidase inhibitor, β-aminopropionitrile (BAPN) fumarate, induces medial degeneration of aorta and results in TAAD formation in mice, characterizing by local dilation of the thoracic aortic wall with a maximum external diameter of >50% compared with the adjacent intact part of the aorta, a tear in the intimal layer of the aorta, extracellular matrix degradation, and inflammation. The pathogenesis of TAAD involves both genetic mutations such as FBN1, LOX, MYH11, and COL3A1 and environmental factors including aging, hypertension, and inflammation. Of note, 2 recent clinical studies indicate that the application of fluoroquinolone antibiotics increases the risk of TAAD. 1, 2 The cause-effect of fluoroquinolone antibiotics to TAAD is further confirmed by supplementation of ciprofloxacin to Ang II (angiotensin II)-infused mice. 3 This alarming observation has raised concern in patients with risk for developing TAAD. Whether other clinical applicable drugs also increase the risk on TAAD progression or rupture?

The Connectivity Map has provided a data-driven and systematic approach for discovering associations among chemicals, genes, and diseases based on genome-wide expression profiling. 4 In principle, drugs with similar gene expression signatures may share similar mechanisms, chemical and physiological processes, and efficacies for similar diseases. By using 6 different fluoroquinolone antibiotics including pefloxacin, ofloxacin, ciprofloxacin, norfloxacin, lomefloxacin, and enoxacin as baits, we found that panobinostat and cefixime exhibited high degree of similarity with fluoroquinolones based on the Spearman correlation score by the Connectivity Map sorting algorithm (Figure [A] ). Panobinostat is a pan-HDAC (histone deacetylase) inhibitor clinically applied for multiple myeloma therapy, and its Spearman similarity score was 0.577. Cefixime is a third-generation cephalosporin antibiotic, and its Spearman similarity score was 0.565. We examined whether these two drugs exhibited deleterious effects on TAAD in a BAPN-induced mouse model. C57BL/6J male mice aged 3 weeks were fed a normal laboratory diet and administered freshly prepared BAPN solution dissolved in the drinking water (0.5 g/kg per day) for consecutive 28 days. The mice were randomly divided into 7 groups: control, panobinostat, cefixime, BAPN, BAPN+ciprofloxacin, BAPN+panobinostat, and BAPN+cefixime. After 28 days, panobinostat and cefixime alone had no obvious changes compared with the control group. BAPN administration caused 33% (12/36) incidence of TAAD, including 11% (4/36) rupture and premature death in mice. Consistent with the previous report in which ciprofloxacin exacerbated TAAD in Ang II-infused mice, 3 the application of ciprofloxacin in mice showed an increasing trend of the incidence of BAPN-induced TAAD (67% [8/12; P=0.088] incidence), including 17% (2/12; P=0.22) rupture and premature death in mice, and used it as a positive control. Intriguingly, the incidence of TAAD in mice of the BAPN+panobinostat group was increased to 76% Inhibition of the HDAC activity has been proposed as a promising therapeutic avenue in the treatment of cancers or cardiovascular diseases. Selective HDAC inhibitors such as class I selective HDAC inhibitors MCT-1 and MS-275 and class II selective HDAC inhibitor MC-1568 have been reported to reduce the pathogenesis and progression of abdominal aortic aneurysm in Ang IIinfused ApoE −/− mice. 5 However, our results identified that MS-275 and MC-1568 had no effect on BAPNinduced TAAD (Figure [B through D] ). Beyond the HDAC family members targeted by MS-275 and MC-1568, pan-HDAC inhibitors additionally inhibit HDAC2, 8, 10, and 11. The inhibition of these HDACs might mediate the pathogenic effect of pan-HDAC inhibitors in TAAD, which requires further investigation.

Our study pointed out that pan-HDAC inhibitors like panobinostat, TSA, and SAHA increased the susceptibility of TAAD in mice. Of note, panobinostat, TSA, and SAHA alone did not induce spontaneous TAAD in mice, but each of them increased the incidence and severity of BAPN-induced TAAD. In accordance, our finding urged that the patients with TAAD or individuals at risk for developing TAAD should be precautious with pan-HDAC inhibitor treatment in their medical therapies. 

Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study

Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone

Effect of ciprofloxacin on susceptibility to aortic dissection and rupture in mice

The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors

Nonparametric Kruskal-Wallis test with a Dunn multiple comparisons test was applied for comparison of the elastin degradation grade. Scale bar, 50 μm. The black arrows indicate the fragmented elastin. F, Representative images of immunofluorescence staining and quantification for CD68 (biomarker of macrophages)-positive (red) in aortas from mice with the indicated administration (n=10 for BAPN+TSA and n=6 for the other groups). Two-way ANOVA was applied to compare the macrophage infiltration. Nuclei were stained with DAPI (4',6-diamidino-2-phenylindole; blue). Scale bar, 25 μm. The white arrows indicate CD68-positive cells. Animal studies were approved by the Animal Care and Use Committee of Peking University. All data have been analyzed for normality and equal variance as a justification for using parametric analysis

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