Pauler Ákos és az ókortudomány

<p>(A) Oil Red O stained cross sections of aortic arch from ApoE^-/- mice after 13 weeks of WD + SHS, WD only, Chow + SHS, and Chow only. Wild type mice fed Chow with and without SHS exposure are shown as controls (WT + SHS, WT Air). Four to six ApoE^-/- mice per group were examined along with 3 WT mice per group. (B) Movat’s Pentachrome stained cross sections of aortic arch from ApoE^-/- mice after 13 weeks of WD + SHS, WD only, Chow + SHS, and Chow only. Three to four mice per group were examined.</p

Metalloproteinase-9 contributes to endothelial dysfunction in atherosclerosis via protease activated receptor-1

<div><p>The atherosclerotic process begins when vascular endothelial cells undergo pro-inflammatory changes such as aberrant activation to dysfunctional phenotypes and apoptosis, leading to loss of vascular integrity. Our laboratory has demonstrated that exposure of mice to second hand smoke triggers an increase in expression of metalloproteinase-9. Further, metalloproteinase-9 released by second hand smoke—activated leukocytes may propagate pro-atherogenic alterations in endothelial cells. We have shown that levels of metalloproteinase-9 were increased in the plasma from apolipoprotein E deficient (ApoE^-/-) mice exposed to second hand smoke relative to non-exposed controls. Moreover, we have collected data from two different, but complementary, treatments of second hand smoke exposed atherosclerotic mice. Animals received either cell specific metalloproteinase-9 directed siRNA to minimize metalloproteinase-9 expression in neutrophils and endothelial cells, or a pharmacological inhibitor of Bruton’s tyrosine kinase which indirectly limits metalloproteinase-9 production in neutrophils. These treatments reduced atherosclerotic changes in mice and improved overall vascular health. We also demonstrated that metalloproteinase-9 could activate endothelial cells and induce their apoptosis via cleavage of protease activated receptor-1. In summary, better understanding of metalloproteinase-9’s pathogenic capabilities as well as novel signaling pathways involved may lead to development of treatments which may provide additional benefits to atherosclerosis patients with a history of second hand smoke exposure.</p></div

Level of MMP-9 (total and endogenous active) in plasma of WD + SHS exposed ApoE^-/- mice.

<p>(A) Total MMP-9 in plasma at 7 weeks and endogenous active MMP-9 at 13 weeks exposure. Values are shown as mean ± STD, † p<0.1, ‡ p<0.05. For 7 weeks groups n = 5, for 13 weeks groups n = 6. (B) Comparison of endogenous active MMP-9 in plasma after 7 and 13 weeks exposure. Values are shown as mean ± STD, * p<0.01. For 7 weeks groups n = 5, for 13 weeks groups n = 6. (C) Gelatin zymography of pooled plasma taken after 5 to 20 weeks exposure, stained gel is shown along with inversion image and corresponding densitometry analysis of the most prominent band (indicated with arrow). For pooling plasma n = 4 at 5 weeks, n = 6 at 13 weeks, and n = 5 for remaining time points.</p

Histological analysis of aortic arch cross sections from ApoE^-/- mice following two week treatments.

<p>(A) Representative sections of aortic arch show atherosclerotic lesions found at the initial branch of the innominate artery of control and treated mice, 5 mice per group were analyzed. Movat’s Pentachrome and Picro-Sirius red stained sections are also shown. (B) Representative Picro-Sirius red stained sections of aortic arches show atherosclerotic lesions found at the innominate artery branch of control and treated mice when viewed under polarized light. (C) Representative sections of aortic arches show atherosclerotic lesions found at the lesser curvature of control and treated mice. Movat’s Pentachrome and Picro-Sirius red stained sections are also shown; 4–5 animals per group were evaluated. (D) Representative Picro-Sirius red stained sections of aortic arches show atherosclerotic lesions found at the lesser curvature in control and treated mice when viewed under normal (right) and polarized (left, center) light; 4–5 animals per group were evaluated.</p

Picro-Sirius red stained cross sections of aortic arch viewed under polarized light.

<p>Aortic arch sections were examined from ApoE^-/- mice after 13 weeks of WD + SHS, WD only, Chow + SHS, and Chow only. Wild type mice fed rodent chow with and without smoke exposure are shown as controls (WT + SHS, WT Air). For ApoE^-/- mice 5–6 mice group were examined, 3 WT mice per group were examined.</p

Histological analysis of aortic arch cross sections at the initial branch of the innominate artery from ApoE^-/- mice following four week treatments.

<p>(A) Representative Oil Red O stained sections of aortic arch show atherosclerotic lesions found at the initial branch of the innominate artery of control and treated mice; 4–8 animals per group were analyzed. Neutral lipids stained red. Movat’s Pentachrome and Picro-Sirius red stained sections of aortic arch are also shown; 3–5 mice per group were analyzed. (B) Representative Picro-Sirius red stained sections of aortic arch show atherosclerotic lesions found at the innominate artery of control and treated mice when viewed under normal (right) and polarized (left, center) light; 3–5 animals were evaluated per group.</p

Histological analysis of aortic arch cross sections at the lesser curvature from ApoE^-/- mice following four week treatments.

<p>(A) Representative Oil Red O stained sections of aortic arch show atherosclerotic lesions found at the lesser curvature of the aortic arch in control and treated mice; 5–8 animals were analyzed per group. Neutral lipids stained red. Movat’s Pentachrome and Picro-Sirius red stained sections are also shown. Four control animals, 5 BTK inhibitor, and 5 MECA:siMMP-9 treated animals were evaluated. (B) Representative Picro-Sirius red stained sections of aortic arches show atherosclerotic lesions found at the lesser curvature of control and treated mice viewed under polarized light. Four control animals, 5 BTK inhibitor, and 5 MECA:siMMP-9 treated animals were evaluated.</p

Changes in plasma levels of chemokines (KC, MCP-1, CRP and ICAM-1).

<p>Changes in plasma levels of chemokines (KC and monocyte chemotactic protein-1 [MCP-1]), C-reactive protein (CRP), and adhesion molecules (intercellular adhesion molecule, ICAM-1) at 13 weeks post WD and / or SHS exposure. Values are shown as mean ± STD, * p<0.01, ‡ p<0.05, † p<0.1. For WD + SHS group n = 5, Chow + SHS and WD Only groups n = 6.</p

Changes in plasma levels of chemokines (KC, MCP-1), CRP, and ICAM-1.

<p>Changes in plasma levels of chemokines (KC and monocyte chemotactic protein-1 [MCP-1]), C-reactive protein (CRP), and adhesion molecules (intercellular adhesion molecule, ICAM-1) at 9 and 11 weeks post WD and / or SHS exposure with and without treatments. BTK Inh. n = 6, MECA n = 4, 11wk WD+SHS n = 9, 11wk WD only n = 5, 9wk WD+SHS n = 5, 9wk WD only n = 5, Ly6G n = 4.</p

MMP-9 activation of endothelial cells.

<p>(A) Effect of stimulation with MMP-9 on HUVEC cell activation (pERK); n = 4. (B) Effect of stimulation with MMP-9 on HUVEC cell apoptosis (caspase-3 activity; p<0.005); n = 6 (C) Expression of MMP-9 and CC3 in aortic leaflets from patients with atherosclerosis; n = 3.</p