Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w

Nitro-oleic acid attenuates thoracic aortic dilation in a murine model of Marfan syndrome through inhibition of MMP-mediated elastin fragmentation

F. Nettersheim1, J. Lemties1, S. Braumann1, S. Geissen1, S. Bokredenghel1, R. J. Nies1, H. Winkels1, B. Freeman2, A. Klinke3, V. Rudolph3, S. Baldus4, D. Mehrkens1, M. Mollenhauer1, M. Adam1

1Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Köln; 2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, US; 3Allgemeine und Interventionelle Kardiologie/Angiologie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; 4Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin, Herzzentrum der Universität zu Köln, Köln;

Background: Formation of thoracic aortic aneurysms is the most threatening complication of Marfan Syndrome (MFS), a relatively common inherited connective tissue disorder. Due to potential occurrence of fatal aortic ruptures and dissections, patients face an increased risk of premature mortality. Despite recent progress in understanding the pathophysiology of MFS-related aortic disease, specific pharmacotherapies are still lacking. MFS is caused by mutations in the Fibrillin-1 (FBN1) gene, which encodes the homonymous extracellular matrix protein FBN1. FBN1 is a key component of elastic fibres and significantly contributes to aortic stability and elasticity. Besides acting as a structural protein, FBN1 is critically involved in tissue homeostasis by sequestration of signalling proteins, such as transforming growth factor beta (TGF-β). Due to FBN1 mutations, TGF-β release from the extracellular matrix is dysregulated in MFS. Of note, increased TGF-β signalling, particularly via the Extracellular-signal Regulated Kinases 1/2 (ERK 1/2) mediated non-canonical pathway, has been identified to drive aortic dilation through induction of matrix metalloproteases (MMPs). Nitro-oleic acid (NO2-OA) is an endogenously formed lipid molecule which elicits posttranslational modifications of regulatory proteins and thus modulates several signalling pathways. Administration of NO2-OA has proven beneficial in various preclinical disease models and the compound, which may be delivered orally, is currently undergoing clinical testing in patients with pulmonary hypertension and glomerulosclerosis. Given that NO2-OA has been repeatedly shown to target ERK1/2, we hypothesized that it may limit aortic dilation in MFS. Methods and Results: NO2-OA or vehicle were subcutaneously administered to eight-week-old male FBN1C1041G/+ mice, heterozygous for a missense mutation in FBN1 (MFS mice), via osmotic minipumps for four weeks and aortic diameters were measured echocardiographically. Compared to vehicle-treated WT littermates, MFS mice exhibited enlarged ascending aortae at baseline and significant progression of aortic dilation during the four-week treatment period. Additionally, aortic pulse wave velocity (PWV), a marker of wall stiffness, was increased in MFS mice. NO2-OA treatment significantly attenuated ascending aortic dilation and reduced PWV back to WT levels. Mechanistically, this therapeutic effect was shown to be mediated by inhibition of aortic ERK1/2 as well as nuclear factor kappa B (NF-κB) activation. Consequently, NO2-OA reduced MFS-related aortic overexpression of MMP 2/9 and NADPH oxidase (NOX) mRNA, which are downstream targets of ERK1/2, as well as inducible nitric oxide synthase (NOS2) mRNA, a downstream target of NF-κB. NO2-OA dependent downregulation of NOX and NOS2 was associated with reduced generation of reactive oxygen species and nitric oxide, that have recently been demonstrated to promote aortic dilation in MFS through increased activation of MMPs. In line with this, NO2-OA treated mice exhibited decreased MMP activity and elastin fragmentation in the ascending aorta. Conclusions: NO2-OA mitigates progression of aortic dilation in MFS through inhibition of ERK1/2 as well as NF-κB signalling and concomitant reduction of MMP-mediated elastin fragmentation. Given these promising data and the shortage of available therapies, utilization of NO2-OA as a treatment for MFS merits further investigation.

https://dgk.org/kongress_programme/jt2021/aP1477.html