Activin A in Degenerative Aortic Valve Disease and Diabetes

Objectives: Activin A is part of the TGFβ superfamily and is known to be involved in fibrotic and degenerative processes of the heart. Nevertheless, its role in aortic valve disease is not yet clear. Own preliminary data show that activin A is upregulated in degenerated human aortic valves. Moreover, activin A treatment leads to an induction of fibrotic markers of valvular interstitial cells (VIC) in vitro. Activin A is also involved in diabetes-induced cardiomyopathies and our data show an upregulation of activin A in degenerated aortic valves of diabetics. Thus, the aim of this study was to evaluate the impact of diabetic conditions on activin A signaling and on remodeling and degenerative processes of VIC in an established in vitro model of diabetes.

Methods: VIC were treated with activin A in combination with hyperglycemia and hyperinsulinemia to induce diabetic conditions. Western blot and gene expression analysis was performed to detect phosphorylation and expression of SMAD2/3/7 and p38 MAPK. Gene expression analysis and a colorimetric assay were used to detect changes of matrix remodeling and degenerative markers in VIC.

Result: SMAD2, SMAD3, and p38 MAPK phosphorylation as well as osteopontin, matrix metalloproteinase 9 and TGFβ expression is increased by activin A but not by diabetic treatment. Expression of matrix metalloproteinase 2 and collagen type 1 as well as calcium accumulation remained unchanged. SMAD7 expression shows an upregulation by diabetic treatment under activin A stimulation. Finally, diabetic treatment leads to a decrease of matrix metalloproteinase 9 and to an increase of TGFβ expression under activin A stimulus.

Conclusion: Activin A treatment leads to an activation of the SMAD2/3 pathway in VIC and chondro-osteogenic markers. Under diabetic conditions, SMAD7 is upregulated, which might be indicative for a protective negative feedback mechanism. Moreover, markers for remodeling and chondro-osteogenic differentiation are regulated in VIC under diabetic conditions, implicating a possible role of activin A in the onset of aortic valve disease in the course of diabetes.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
19 February 2021