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    • Gene regulation of MMPs is influenced by the transcription f

    2023-09-15

    Gene regulation of MMPs is influenced by the transcription factor activating factor-1 (AP-1). AP-1 complexes are heterodimers of proteins of the two proto-oncogene families (jun and fos) and have bioactive in the promoter region of MMPs, as well as in genes mediating inflammatory responses. The transcription factor decoy oligodeoxynucleotide (dODN) methodology allows neutralization of AP-1 and thereby inhibition of target gene expression, which has already been demonstrated by several preclinical animal studies. dODNs are taken up efficiently by their target cells without any delivery aid through an energy-dependent carrier-mediated transport mechanism. These short double-stranded DNA sequences have successfully been used to bind specifically and neutralize transcription factors in cultured cells or in vivo, rendering them incapable of subsequent binding to the promoter region and induce the expression of target genes. We hypothesized that ex vivo aortic AP-1 neutralization by anti-AP-1 dODN leads to reduction of MMP expression and therefore reduces aortic elastolysis in an aortic transplantation murine Marfan model (mgR/mgR). Here, we report that in explanted aortic grafts of mgR/mgR mice pretreated with AP-1 dODN MMP activity and elastic fiber degradation were significantly decreased.
    Results
    Discussion Aortic root dilatation may lead to aortic rupture or dissection as the most life-limiting factor in Marfan syndrome. These patients need lifelong clinical and imaging surveillance, and operation for life-threatening aortic root dilatation is with few exceptions inevitable. New operative concepts such as aortic-valve-preserving implantation techniques for replacement of the aneurysmatic aortic root have shown favorable results; however, the underlying vascular pathology is not affected by surgery and the elastolysis may progress in the downstream aorta. Throughout the last years, medical treatment options changed from β-adrenergic blocker and calcium antagonists to doxycycline and losartan therapy with new insights in the pathomechanism of aortic wall degradation. Also statins, as HMG-CoA reductase inhibitors, accomplish similar effects to losartan in attenuating aortic root dilatation in a murine model of Marfan syndrome by reduction of MMPs. Interestingly, statins are also known to downregulate the activation of AP-1, which would explain the therapeutic effect that we have demonstrated here in Marfan mice. Deeper understanding of the pathology and molecular mechanisms of the vascular phenotype in MFS may help to develop new treatment strategies aiming to prevent root dilatation and consecutive need for open-heart surgery. Disturbances in different molecular pathways caused by the underlying Fbn1 mutation may be responsible for the elastolysis of the aortic wall. To assess mechanisms and treatment options, various murine models of Marfan syndrome have been developed. The hypomorphic mgR/mgR mouse provides a model with about only a quarter of Fbn1 production leading to phenotypic features in the skeleton and the aorta similar to those of patients with classic MFS. Recently, we were able to show that 49 out of 50 mgR/mgR mice die due to rupture and dissection of the ascending aorta. MMPs are presumed to play a key role in the pathogenesis of this genetic disorder through an imbalance between synthesis and proteolysis of extracellular matrix of the aortic media. MMP-2 and MMP-9 as elastolytic MMPs are secreted by AoSMC into the aortic media. Chung et al. demonstrated that elevated expression of MMP-2 and -9 lead to progression of thoracic aortic aneurysms associated with degeneration of elastic fibers, endothelial dysfunction, and reduced SMC contractility. MMP-2 and -9 have also been associated with TGF-β activation, which connects both MMP and TGF-β as the two major contributors of aortic elastolysis in Marfan patients. AP-1 has been described to be a downstream mediator of TGF-β signaling and profibrotic effects pointing out the potential importance of AP-1 in Marfan syndrome.