DUSP26 induces aortic valve calcification by antagonizing MDM2-mediated ubiquitination of DPP4 in human valvular interstitial cells

Abstract

Aims The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited. Here, we evaluated the role and therapeutic value of dual-specificity phosphatase 26 (DUSP26) in CAVD. Methods and results Microarray profiling of human calcific aortic valves and normal controls demonstrated that DUSP26 was significantly up-regulated in calcific aortic valves. ApoE−/− mice fed a normal diet or a high cholesterol diet (HCD) were infected with adeno-associated virus serotype 2 carrying DUSP26 short-hairpin RNA to examine the effects of DUSP26 silencing on aortic valve calcification. DUSP26 silencing ameliorated aortic valve calcification in HCD-treated ApoE−/− mice, as evidenced by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased peak transvalvular jet velocity and mean transvalvular pressure gradient, as well as increased aortic valve area), and decreased levels of osteogenic markers (Runx2, osterix, and osteocalcin) in the aortic valves. These results were confirmed in osteogenic medium-induced human valvular interstitial cells. Immunoprecipitation, liquid chromatography-tandem mass spectrometry, and functional assays revealed that dipeptidyl peptidase-4 (DPP4) interacted with DUSP26 to mediate the procalcific effects of DUSP26. High N6-methyladenosine levels up-regulated DUSP26 in CAVD; in turn, DUSP26 activated DPP4 by antagonizing mouse double minute 2-mediated ubiquitination and degradation of DPP4, thereby promoting CAVD progression. Conclusion DUSP26 promotes aortic valve calcification by inhibiting DPP4 degradation. Our findings identify a previously unrecognized mechanism of DPP4 up-regulation in CAVD, suggesting that DUSP26 silencing or inhibition is a viable therapeutic strategy to impede CAVD progression.

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

“…Genome-wide association study (GWAS), however, have revealed a single nucleotide polymorphism with a strong independent predictive association with the development of AS; and multi-omics study has identified potential effector proteins and expressed genes linking Lp(a) to valvular calcification ( 206 , 207 ). Wang et al utilised multi-omic screening of explanted human aortic valve specimens to identify dual-specificity phosphatase 26 (DUSP26) as an upregulated gene promoting aortic valve calcification in CAVD, subsequently using in vivo mouse and in vitro human VIC studies to confirm that DUSP26 promotes CAVD via upregulation of dipeptidyl peptidase 4 (DPP4) ( 208 ). Moving forward, multi-omics studies have great potential to identify genes, proteins and small molecules that may be targetted in medical treatment for CAVD.…”

“…In addition to identifying new molecular targets, existing therapeutic agents may be repurposed in the treatment of CAVD ( 209 ). As mechanistic studies identify new mediators of CAVD, existing drugs such as DPP4 inhibitors currently used in the treatment of diabetes may become candidates for the treatment of CAVD ( 208 ). Similarly, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have shown efficacy in the treatment of coronary artery disease, and upregulation of PCSK9 has been identified in human CAVD and promotes VIC calcification in vitro ( 210 ).…”

An Unconventional Ligand for Scribble PDZ-4 Domain Mediates Its Interaction with Dusp26

“…However, the molecular mechanism that determines the target specificity of these enzymes is far from being elucidated, and too often the exact dephosphorylated residue is unknown, as is the phosphatase region that allows for the recognition. This knowledge is crucial for any clinical application, in order not to mislead the models, particularly for Dusp26 that has been recently associated with different pathologies such as cancer, as well as metabolic and neurodegenerative disorders [49,50]. Despite the fact that Dusp26, as many other phosphatases, has been considered an "undruggable" target, three chemical inhibitors of Dusp26 have been reported in literature.…”

Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α

“…Dysfunctional expression of ubiquitin E3 ligases, which mainly determines the specificity and rate-limiting step of ubiquitination, plays an essential role in the pathological processes of various diseases [ 8 , 9 ]. Regulating the levels of ubiquitin E3 ligases has been proven to be able to treat many cardiovascular diseases, such as cardiac hypertrophy, valve calcification, and pulmonary arterial hypertension [ 10 – 12 ].…”