Background:
Atherosclerosis and diabetes share many common pathogenic mechanisms. Vascular calcification is a common and severe complication in patients with atherosclerosis and type-2 diabetes (T2D), and occurs when vascular smooth muscle cells (VSMCs) trans-differentiate into osteoblast-like cells, in a process driven by runt-related transcription factor-2 (RUNX2). Our laboratory has recently discovered that Discoidin Domain Receptor-1 (DDR1) deletion reduces vascular calcification
in vivo
in
Ldlr
-/-
mice. Additionally, we have shown that RUNX2 activity is reduced in
Ddr1
-/-
VSMCs. However, little is known about the mechanism by which DDR1 mediates calcification and RUNX2 activity.
Rationale:
The insulin signaling pathway plays an important role in T2D and VSMC function. It has recently been discovered that PI3K binds to the DDR1 tyrosine kinase domain upon DDR1 activation.
Hypothesis:
DDR1 promotes vascular calcification by inducing RUNX2 activity via the PI3K/Akt signaling pathway in T2D.
Methods/Results:
To study the role of DDR1 in vascular calcification in T2D,
Ldlr
-/-
(SKO) and
Ldlr-/-; Ddr1
-/-
(DKO) mice were placed on a modified Western diet (40% fat, 43% carbohydrates, 0.5% cholesterol) for 12 weeks. Oil Red-O staining of the descending aorta showed reduced plaque burden in DKO mice (9.1±2.7% vs 4.4±2.9% surface area; p<0.05). Measurements of vascular calcification are ongoing. To determine the mechanism by which DDR1 modulates VSMC calcification, primary VSMCs collected from
Ddr1
+/+
and
DDR1
-/-
mice were cultured in osteogenic media for 12 days to induce calcification. Proliferation and calcification were significantly reduced in
DDR1
-/-
VSMCs. Additionally,
DDR1
-/-
VSMCs showed significantly reduced p-Akt levels when stimulated with insulin.
Significance:
Current treatments for vascular calcification are non-specific and often pose a risk to bone health. This is the first study to test the role of DDR1 in vascular calcification in an animal model of T2D, which will provide novel insight into the mechanism of vascular calcification and uncover new potential therapeutic approaches.
Role of periostin and discoidin domain receptor-1 (DDR1) in the regulation of cartilage degeneration and expression of MMP-13
