The Protective Role of Yin‐Yang 1 in Cardiac Injury and Remodeling After Myocardial Infarction

Background Exploring potential therapeutic target is of great significance for myocardial infarction (MI) and post‐MI heart failure. Transcription factor Yin‐Yang 1 (YY1) is an essential regulator of apoptosis and angiogenesis, but its role in MI is unclear. Methods and Results The expression of YY1 was assessed in the C57BL/6J mouse heart following MI. Overexpression or silencing of YY1 in the mouse heart was achieved by adeno‐associated virus 9 injection. The survival, cardiac function, and scar size, as well as the apoptosis, angiogenesis, cardiac fibrosis, T helper 2 lymphocyte cytokine production, and macrophage polarization were assessed. The effects of YY1 on Akt phosphorylation and vascular endothelial growth factor production were also investigated. The expression of YY1 in heart was significantly stimulated by MI. The survival rate, cardiac function, scar size, and left ventricular volume of mice were improved by YY1 overexpression but worsened by YY1 silencing. YY1 alleviated cardiac apoptosis and fibrosis, promoted angiogenesis, T helper 2 cytokine production, and M2 macrophage polarization in the post‐MI heart, it also enhanced the tube formation and migration ability of endothelial cells. Enhanced Akt phosphorylation, along with the increased vascular endothelial growth factor levels were observed in presence of YY1 overexpression. Conclusions YY1 ameliorates cardiac injury and remodeling after MI by repressing cardiomyocyte apoptosis and boosting angiogenesis, which might be ascribed to the enhancement of Akt phosphorylation and the subsequent vascular endothelial growth factor up‐regulation. Increased T helper 2 cytokine production and M2 macrophage polarization may also be involved in YY1’s cardioprotective effects. These findings supported YY1 as a potential target for therapeutic investigation of MI.

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Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Molecular Biology of the Cell ◽

10.1091/mbc.e08-10-1005 ◽

2009 ◽

Vol 20 (5) ◽

pp. 1280-1288 ◽

Cited By ~ 104

Author(s):

Nicole Weis ◽

Andreas Weigert ◽

Andreas von Knethen ◽

Bernhard Brüne

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Heme Oxygenase ◽

Apoptotic Cell ◽

Macrophage Polarization ◽

Heme Oxygenase 1 ◽

M2 Macrophage ◽

Vascular Endothelial ◽

Anti Inflammatory ◽

Endothelial Growth Factor

Apoptotic cells (AC) are rapidly engulfed by professional phagocytes such as macrophages to avoid secondary necrosis and thus inflammation. Recognition of AC polarizes macrophages toward an anti-inflammatory phenotype, which shows homology to an alternatively activated M2 macrophage. However, mechanistic details provoking these phenotype alterations are incompletely understood. Here, we demonstrate a biphasic up-regulation of heme oxygenase-1 (HO-1), a protein that bears an antiapoptotic as well as an anti-inflammatory potential, in primary human macrophages, which were exposed to the supernatant of AC. Although the first phase of HO-1 induction at 6 h was accomplished by AC-derived sphingosine-1-phosphate (S1P) acting via S1P receptor 1, the second wave of HO-1 induction at 24 h was attributed to autocrine signaling of vascular endothelial growth factor A (VEGFA), whose expression and release were facilitated by S1P. Whereas VEGFA release from macrophages was signal transducer and activator of transcription (STAT) 1-dependent, vascular endothelial growth factor itself triggered STAT1/STAT3 heterodimer formation, which bound to and activated the HO-1 promoter. Knockdown of HO-1 proved its relevance in facilitating enhanced expression of the antiapoptotic proteins Bcl-2 and Bcl-XL, as well as the anti-inflammatory adenosine receptor A2A. These findings suggest that HO-1, which is induced by AC-derived S1P, is critically involved in macrophage polarization toward an M2 phenotype.

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Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00504.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. C821-C827 ◽

Cited By ~ 39

Author(s):

Qin Hao ◽

Linping Wang ◽

Hua Tang

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Protein Kinase ◽

Proinflammatory Cytokines ◽

Proinflammatory Cytokine ◽

Cytokine Production ◽

Protein Kinase D ◽

Vascular Endothelial ◽

Endothelial Growth Factor

Emerging evidence indicates that vascular endothelial growth factor (VEGF) plays a critical role in host inflammatory responses in several disease states, including atherosclerosis, sepsis, and rheumatoid arthritis. In this study, we determined the effect of VEGF on endothelial induction of proinflammatory cytokines and investigated the responsible signal pathways. By using a cytokine antibody array that detects the end point protein products released from endothelial cells (ECs), we found that VEGF, via VEGF receptor 2 (VEGFR2), predominantly induced the production of proinflammatory cytokine interleukin (IL)-6 and CXC chemokines IL-8 and growth-related oncogene-α (GRO-α) in ECs but not in leukocytes among 36 cytokines in the array. The production of these inflammatory cytokines by VEGF was much stronger than the induction of cell adhesion molecule in ECs. We further found that the cytokine production by VEGF was essentially mediated by the Gö-6976-sensitive protein kinase D (PKD) family kinases. Importantly, the VEGF-induced production of IL-6, IL-8, and GRO-α was inhibited ∼70%, 40%, or 37% by PKD1 silencing (more than 90% knockdown) with three small interference RNAs that target different PKD1 regions. Moreover, silencing PKD2 downregulated VEGFR2 and markedly inhibited the cytokine production by VEGF in ECs. Our results indicate that VEGF, via VEGFR2-PKD1 axis, induces the production of proinflammatory cytokine IL-6, IL-8, and GRO-α in ECs but not in leukocytes, which may offer new insights into the mechanism of the proinflammatory activity of VEGF.

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