Loss of SPRR3 in ApoE-/- mice leads to atheroma vulnerability through Akt dependent and independent effects in VSMCs.

Lietman CD, Segedy AK, Li B, Fazio S, Atkinson JB, Linton MF, Young PP
PLoS One. 2017 12 (9): e0184620

PMID: 28886156 · PMCID: PMC5590986 · DOI:10.1371/journal.pone.0184620

Vascular smooth muscle cells (VSMCs) represent important modulators of plaque stability in advanced lesions. We previously reported that loss of small proline-rich repeat protein 3 (Sprr3), leads to VSMC apoptosis in a PI3K/Akt-dependent manner and accelerates lesion progression. Here, we investigated the role of Sprr3 in modulating plaque stability in hyperlipidemic ApoE-/- mice. We show that loss of Sprr3 increased necrotic core size and reduced cap collagen content of atheromas in brachiocephalic arteries with evidence of plaque rupture and development of intraluminal thrombi. Moreover, Sprr3-/-ApoE-/- mice developed advanced coronary artery lesions accompanied by intraplaque hemorrhage and left ventricle microinfarcts. SPRR3 is known to reduce VSMC survival in lesions by promoting their apoptosis. In addition, we demonstrated that Sprr3-/- VSMCs displayed reduced expression of procollagen in a PI3K/Akt dependent manner. SPRR3 loss also increased MMP gelatinase activity in lesions, and increased MMP2 expression, migration and contraction of VSMCs independently of PI3K/Akt. Consequently, Sprr3 represents the first described VSMC modulator of each of the critical features of cap stability, including VSMC numbers, collagen type I synthesis, and protease activity through Akt dependent and independent pathways.

MeSH Terms (15)

Animals Apolipoproteins E Cornified Envelope Proline-Rich Proteins Female Fibronectins Immunoblotting Mice Mice, Inbred C57BL Mice, Knockout Muscle, Smooth, Vascular Myocytes, Smooth Muscle Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt Real-Time Polymerase Chain Reaction Signal Transduction

Connections (1)

This publication is referenced by other Labnodes entities:

Links