Marfan syndrome ( MFS ) is an autosomal dominant genetic disorder caused by mutations in the FBN 1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS ‐related mortality. Aberrant TGF ‐beta signalling plays a major role in the pathophysiology of MFS . However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta‐specific pathways involved in the pathophysiology of MFS . For this purpose, we employed the Fbn1 under‐expressing mgR/mgR mouse model of MFS . We performed RNA ‐sequencing of aortic tissues of 9‐week‐old mgR/mgR mice compared with wild‐type ( WT ) mice. With a false discovery rate <5%, our analysis revealed 248 genes to be differentially regulated including 20 genes previously unrelated with MFS ‐related pathology. Among these, we identified Igfbp2 , Ccl8 , Spp1 , Mylk2 , Mfap4 , Dsp and H19 . We confirmed the expression of regulated genes by quantitative real‐time PCR . Pathway classification revealed transcript signatures involved in chemokine signalling, cardiac muscle contraction, dilated and hypertrophic cardiomyopathy. Furthermore, our immunoblot analysis of aortic tissues revealed altered regulation of pS mad2 signalling, Perk1/2, Igfbp2, Mfap4, Ccl8 and Mylk2 protein levels in mgR/mgR vs WT mice. Together, our integrative systems approach identified several novel factors associated with MFS ‐aortic‐specific pathophysiology that might offer potential novel therapeutic targets for MFS .
Defects in the extracellular matrix protein fibrillin-1 that perturb transforming growth factor beta (TGFβ) bioavailability lead to Marfan syndrome (MFS). MFS is an autosomal-dominant disorder, which is associated with connective tissue and skeletal defects, among others. To date, it is unclear how biological sex impacts the structural and functional properties of bone in MFS. The aim of this study was to investigate the effects of sex on bone microarchitecture and mechanical properties in mice with deficient fibrillin-1, a model of human MFS. Bones of 11-week-old male and female Fbn1mgR/mgR mice were investigated. Three-dimensional micro-computed tomography of femora and vertebrae revealed a lower ratio of trabecular bone volume to tissue volume, reduced trabecular number and thickness, and greater trabecular separation in females vs. males. Three-point bending of femora revealed significantly lower post-yield displacement and work-to-fracture in females vs. males. Mechanistically, we found higher Smad2 and ERK1/2 phosphorylation in females vs. males, demonstrating a greater activation of TGFβ signaling in females. In summary, the present findings show pronounced sex differences in the matrix and function of bones deficient in fibrillin-1 microfibrils. Consequently, sex-specific analysis of bone characteristics in patients with MFS may prove useful in improving the clinical management and life quality of these patients, through the development of sex-specific therapeutic approaches.
Dichloroacetate (DCA) is a small, orally available inhibitor of pyruvate dehydrogenase kinase (PDK). Consequently, DCA stimulates the activity of the pyruvate dehydrogenase complex (PDC), leading to glucose oxidation in the mitochondria. Therapeutically, DCA is employed to decrease lactate production and has been used in the acute treatment of certain metabolic diseases, such as lactic acidosis. More recently, DCA has been reported to have anti‐cancer efficacy and has been suggested as a chemotherapeutic. However, DCA as a therapeutic agent may have adverse effects, as it has been reported to cause hepatocellular and peripheral nerve toxicity. As it may have further adverse effects when used chronically, there is a need for further investigation of the effects and mechanisms triggered by DCA. We aimed at assessing the effects of chronic DCA administration in the mouse heart. We hypothesized that long‐term treatment of mice with DCA will lead to cardiac toxicity, ultimately contributing to heart failure development, and that the severity of these effects will differ between the sexes. Fourteen‐month old male and female C57Bl6 mice (n = 12/group) were treated with vehicle or DCA (0.8 g/L in drinking water leading to 80 mg/kg/d, similar to clinically used dose) for 7 months. All mice underwent transthoracic 2D echocardiography under anesthesia (isoflurane 2%) following established procedures. The study was conducted in conformance with the FASEB Statement of Principles for the use of Animals in Research and Education. Following the 7‐mo DCA treatment, echocardiographic measurements revealed no major functional effect in female mice. In contrast, male mice treated with DCA exhibited a significant systolic dysfunction associated with impaired contractility compared with control mice (ejection fraction: 36% vs. 47% respectively, P < 0.001). Ultrastructural analysis of left ventricular samples by transmission electron microscopy revealed increased numbers of heavily damaged and swollen mitochondria in male mice treated with DCA, while female mice treated with DCA were not affected. Further cellular characterization revealed no major effects on apoptosis, as assessed by the TUNEL assay, or fibrosis, as assessed by Sirius‐red staining. Transcriptome analysis of left ventricles from vehicle‐ and DCA‐treated mice by genome‐wide expression profiling (n = 5/group, P < 0.001) revealed decreased levels of genes involved in ion channel activity and metabolism in male DCA‐treated mice. In contrast, the levels of genes with antioxidant activity were increased in female DCA‐treated mice. In conclusion, chronic DCA treatment leads to male‐specific cardiac toxicity and dysfunction. These findings highlight the role of biological sex in therapeutic and adverse effects of pharmacological agents.Support or Funding InformationDZHK (German Centre for Cardiovascular Research) and BMBF (Federal Ministry of Education and Research).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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