This study demonstrates the regulatory mechanism of Sp1-mediated MMP-9 expression in diabetic wound healing and highlights the potential therapeutic benefits of miR-129 and -335 in delayed wound healing in diabetes.
The mechanism associated with diabetes and AF may be attributed to oxidative stress (ROS production) derived from NOX activity, and then induced activation of the MAPK signaling pathways and MMP9 expression.
MMP-9 levels correlated with hemoglobin A1c in DKA and diabetes controls, but remained significantly elevated in DKA after controlling for hemoglobin A1c (β = -31.3, p = 0.04).
MMP-9 promoter has binding sites for many transcription factors, and in diabetes its promoter undergoes epigenetic modifications, including histone modifications and DNA methylation.
In a streptozotocin-induced diabetes mouse model, Nrf2(-/-) mice have delayed wound closure rates compared with Nrf2(+/+) mice, which is, at least partially, due to greater oxidative DNA damage, low transforming growth factor-β1 (TGF-β1) and high matrix metalloproteinase 9 (MMP9) expression, and increased apoptosis.
To understand how diabetes increases mitochondrial accumulation of MMP-9, interactions between MMP-9 and chaperone proteins (heat shock protein [Hsp] 70 and Hsp60) were evaluated.
Plasma MMP-9 (p=0.027) and TIMP-1 (p=0.016) concentrations were significantly greater, and the ratio of plasma TIMP-1:MMP-9 concentrations significantly lower, in the diabetes group (p=0.023).
The increased MMP-1, MMP-2 and MMP-9 activities induced by high glucose exposure could promote matrix degradation thereby accelerating atherogenesis and potentially reducing plaque stability in diabetes.
These differences may be contributing to the impaired healing of the diabetes mouse; however, they differ from the human data presented here, which show elevated matrix metalloproteinase 2 and reduced matrix metalloproteinase 9 in human diabetic chronic wound fluid compared to acute wound fluid.