Deletion of Periostin Protects Against Atherosclerosis in Mice by Altering Inflammation and Extracellular Matrix Remodeling

Abstract

Objective Periostin is a secreted protein that can alter extracellular matrix remodeling in response to tissue injury. However, the functional role of periostin in the development of atherosclerotic plaques has yet to be described despite its observed induction in diseased vessels and presence in the serum. Approach and Results Hyperlipidemic, apolipoprotein E-null mice (ApoE−/−) were crossed with periostin (Postn−/−) gene-deleted mice and placed on a high fat diet for 6 or 14 weeks to induce atherosclerosis. En face analysis of aortas showed significantly decreased lesion areas of ApoE−/− Postn−/− mice compared to ApoE−/− mice, as well as a reduced inflammatory response with less macrophage content. Moreover, diseased aortas from ApoE−/− Postn−/− mice displayed a disorganized extracellular matrix with less collagen cross linking and smaller fibrotic caps, as well as increased matrix metalloprotease-2, matrix metalloprotease-13, and procollagen-lysine, 2-oxoglutarate 5-dioxygenase-1 mRNA expression. Furthermore, loss of periostin was associated with a switch in vascular smooth muscle cells towards a more proliferative and synthetic phenotype. Mechanistically, loss of periostin reduced macrophage recruitment by transforming growth factor-β in cellular migration assays. Conclusions These are the first genetic data detailing the function of periostin as a regulator of atherosclerotic lesion formation and progression. The data suggest that periostin could be a therapeutic target for atherosclerotic plaque formation through modulation of the immune response and extracellular matrix remodeling.

Osteopontin lung gene expression is a marker of disease severity in pulmonary arterial hypertension

“…Recent evidence points to an important role of components of the ECM from both a biomarker and a therapeutic prospective in PAH . The most upregulated gene in severe PAH was indeed periostin, another matricellular protein involved in response to vascular injury and regulation of SMC proliferation . Chronic normobaric hypoxic exposure for 2 weeks significantly increased the mRNA level of periostin in the rat lung and hypoxia‐induced periostin expression was localized to PA‐SMC of hypertrophic PA.…”

Profilin-mediated food-induced allergic reactions are associated with oral epithelial remodeling

“…Although little is known about the exact role of this protein in allergic patients, it has been described as a marker for asthma severity and been associated with epithelial remodeling processes in airway mucosa. [15][16][17]34 Regarding immunologic characteristics, allergic patients had a progressive inflammatory profile. Although allergic responses in the gut and lung mucosa have been investigated, 35 allergic inflammation in the oral mucosa remains largely unexplored.…”

Vascular Smooth Muscle Cells

“…Schwanekamp et al examined the role of periostin, a secreted ECM protein, on the development of atherosclerosis in an ApoE−/− model. 67 These authors found that periostin-deficient, ApoE-null mice developed reduced plaque areas, fewer plaque macrophages, disorganized plaque ECM, thinner fibrotic caps, and increased MMP-2 and MMP-13 levels than ApoE-null control mice. 67 It would be interesting to determine if the reduced number of plaque macrophages observed in the absence of periostin was the result of reduced plaque SMC transition to a macrophage-like phenotype now that the necessary mouse genetic tools are available to test this possibility.…”