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Diabetes alters activation and repression of pro- and anti-inflammatory signaling pathways in the vasculature.

Di Marco E, Gray SP, Jandeleit-Dahm K - Front Endocrinol (Lausanne) (2013)

Bottom Line: We aim to describe the interaction between advanced glycation end products and their principle receptor RAGE, angiotensin II, and the Ang II type 1 receptor, in addition to reactive oxygen species (ROS) production by NADPH-oxidase enzymes that are relevant to vascular and immune cell function in the context of diabetic vasculopathy.Furthermore, we will touch on recent advances in epigenetic medicine that have revealed high glucose-mediated changes in the transcription of genes with known pro-inflammatory downstream targets.Finally, novel anti-atherosclerosis strategies that target the vascular immune interface will be explored; such as vaccination against modified low-density lipoprotein and pharmacological inhibition of ROS-producing enzymes.

View Article: PubMed Central - PubMed

Affiliation: Baker IDI Heart and Diabetes Research Institute , Melbourne, VIC , Australia ; Department of Medicine, Monash University , Melbourne, VIC , Australia.

ABSTRACT
A central mechanism driving vascular disease in diabetes is immune cell-mediated inflammation. In diabetes, enhanced oxidation and glycation of macromolecules, such as lipoproteins, insults the endothelium, and activates both innate and adaptive arms of the immune system by generating new antigens for presentation to adaptive immune cells. Chronic inflammation of the endothelium in diabetes leads to continuous infiltration and accumulation of leukocytes at sites of endothelial cell injury. We will describe the central role of the macrophage as a source of signaling molecules and damaging by-products which activate infiltrating lymphocytes in the tissue and contribute to the pro-oxidant and pro-inflammatory microenvironment. An important aspect to be considered is the diabetes-associated defects in the immune system, such as fewer or dysfunctional athero-protective leukocyte subsets in the diabetic lesion compared to non-diabetic lesions. This review will discuss the key pro-inflammatory signaling pathways responsible for leukocyte recruitment and activation in the injured vessel, with particular focus on pro- and anti-inflammatory pathways aberrantly activated or repressed in diabetes. We aim to describe the interaction between advanced glycation end products and their principle receptor RAGE, angiotensin II, and the Ang II type 1 receptor, in addition to reactive oxygen species (ROS) production by NADPH-oxidase enzymes that are relevant to vascular and immune cell function in the context of diabetic vasculopathy. Furthermore, we will touch on recent advances in epigenetic medicine that have revealed high glucose-mediated changes in the transcription of genes with known pro-inflammatory downstream targets. Finally, novel anti-atherosclerosis strategies that target the vascular immune interface will be explored; such as vaccination against modified low-density lipoprotein and pharmacological inhibition of ROS-producing enzymes.

No MeSH data available.


Related in: MedlinePlus

Immune mechanisms engaged in diabetes-accelerated atherosclerosis. Diabetes-associated hyperglycemia, hyperlipidemia, and oxidative stress render the endothelium dysfunctional, leading to the retention and oxidation of LDL molecules in the intimal space. The increased expression of adhesion molecules E-selectin, ICAM-1, VCAM-1 at the endothelial membrane, and upregulation of chemotactic molecules such as MCP-1 facilitate the continuous infiltration of immune cells to the inflamed aorta. Resident and monocyte-derived macrophages engulf LDL to form foam cells which release a host of pro-inflammatory cytokines, protease, and ROS. Activated T cells recruited from the circulation to the lesion also secrete cytokines which amplify pro-inflammatory cellular immune responses in the diabetic plaque. The diabetes-mediated increase in vascular inflammation drives the development and progression of atherosclerosis. AGEs, advanced glycation end-products; AT1R, angiotensin II type 1 receptor; ICAM-1, intercellular adhesion molecule-1; LDL, low-density lipoprotein; MCP-1, monocyte chemotactic protein-1; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; VCAM-1, vascular cell adhesion molecule-1.
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Figure 1: Immune mechanisms engaged in diabetes-accelerated atherosclerosis. Diabetes-associated hyperglycemia, hyperlipidemia, and oxidative stress render the endothelium dysfunctional, leading to the retention and oxidation of LDL molecules in the intimal space. The increased expression of adhesion molecules E-selectin, ICAM-1, VCAM-1 at the endothelial membrane, and upregulation of chemotactic molecules such as MCP-1 facilitate the continuous infiltration of immune cells to the inflamed aorta. Resident and monocyte-derived macrophages engulf LDL to form foam cells which release a host of pro-inflammatory cytokines, protease, and ROS. Activated T cells recruited from the circulation to the lesion also secrete cytokines which amplify pro-inflammatory cellular immune responses in the diabetic plaque. The diabetes-mediated increase in vascular inflammation drives the development and progression of atherosclerosis. AGEs, advanced glycation end-products; AT1R, angiotensin II type 1 receptor; ICAM-1, intercellular adhesion molecule-1; LDL, low-density lipoprotein; MCP-1, monocyte chemotactic protein-1; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; VCAM-1, vascular cell adhesion molecule-1.

Mentions: Chronic injury to the endothelium results in endothelial dysfunction, which can be defined as increased permeability, reduced nitric oxide (NO) dependent vasodilatation as well as enhanced pro-thrombotic and pro-inflammatory properties (Hink et al., 2001; Davignon and Ganz, 2004; Hartge et al., 2007). Endothelial dysfunction is a well established precursor of atherosclerosis, particularly in the setting of diabetes (Schalkwijk and Stehouwer, 2005). The diabetes-associated factors that impair normal endothelial function include increased synthesis of vasoconstrictors such as angiotensin II (Ang II) and endothelin-1, uncoupling of endothelial nitric oxide synthase (eNOS; leading to reduced bioavailability of NO), and increased expression and activity of ROS-producing enzymes (such as NADPH oxidases, Nox) which trigger the expression of adhesion and chemotactic molecules that promote the recruitment of inflammatory cells to the arterial wall (Figure 1) (Hink et al., 2001; Guzik et al., 2002; Lüscher et al., 2003; Hartge et al., 2007). Aortic lesions of diabetic ApoE knockout (KO) mice show increased gene expression of pro-inflammatory molecules MCP-1, VCAM-1, and NF-κB subunit p65 associated with increased pro-atherogenic cellularity [macrophages, T cells, and smooth muscle cells (SMCs)] compared to non-diabetic controls (Soro-Paavonen et al., 2008). In line with these in vivo findings, human endothelial cells exposed to high glucose conditions show increased leukocyte binding associated with increased expression of E-selectin, ICAM-1, VCAM-1, and MCP-1 through activation of NF-κB (Kim et al., 1994; Morigi et al., 1998; Piga et al., 2007). In addition, recent studies have revealed a striking association between glucose-induced endothelial expression of adhesion molecules VCAM-1 and P-selectin as well as the chemokines MCP-1 and fractalkine with Nox-derived ROS production (Manduteanu et al., 2010; Gray et al., 2013). These data indicate that diabetes-associated hyperglycemia and oxidative stress promote leukocyte-endothelial cell interactions required for the recruitment of leukocytes to the inflamed vessel.


Diabetes alters activation and repression of pro- and anti-inflammatory signaling pathways in the vasculature.

Di Marco E, Gray SP, Jandeleit-Dahm K - Front Endocrinol (Lausanne) (2013)

Immune mechanisms engaged in diabetes-accelerated atherosclerosis. Diabetes-associated hyperglycemia, hyperlipidemia, and oxidative stress render the endothelium dysfunctional, leading to the retention and oxidation of LDL molecules in the intimal space. The increased expression of adhesion molecules E-selectin, ICAM-1, VCAM-1 at the endothelial membrane, and upregulation of chemotactic molecules such as MCP-1 facilitate the continuous infiltration of immune cells to the inflamed aorta. Resident and monocyte-derived macrophages engulf LDL to form foam cells which release a host of pro-inflammatory cytokines, protease, and ROS. Activated T cells recruited from the circulation to the lesion also secrete cytokines which amplify pro-inflammatory cellular immune responses in the diabetic plaque. The diabetes-mediated increase in vascular inflammation drives the development and progression of atherosclerosis. AGEs, advanced glycation end-products; AT1R, angiotensin II type 1 receptor; ICAM-1, intercellular adhesion molecule-1; LDL, low-density lipoprotein; MCP-1, monocyte chemotactic protein-1; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; VCAM-1, vascular cell adhesion molecule-1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 1: Immune mechanisms engaged in diabetes-accelerated atherosclerosis. Diabetes-associated hyperglycemia, hyperlipidemia, and oxidative stress render the endothelium dysfunctional, leading to the retention and oxidation of LDL molecules in the intimal space. The increased expression of adhesion molecules E-selectin, ICAM-1, VCAM-1 at the endothelial membrane, and upregulation of chemotactic molecules such as MCP-1 facilitate the continuous infiltration of immune cells to the inflamed aorta. Resident and monocyte-derived macrophages engulf LDL to form foam cells which release a host of pro-inflammatory cytokines, protease, and ROS. Activated T cells recruited from the circulation to the lesion also secrete cytokines which amplify pro-inflammatory cellular immune responses in the diabetic plaque. The diabetes-mediated increase in vascular inflammation drives the development and progression of atherosclerosis. AGEs, advanced glycation end-products; AT1R, angiotensin II type 1 receptor; ICAM-1, intercellular adhesion molecule-1; LDL, low-density lipoprotein; MCP-1, monocyte chemotactic protein-1; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; VCAM-1, vascular cell adhesion molecule-1.
Mentions: Chronic injury to the endothelium results in endothelial dysfunction, which can be defined as increased permeability, reduced nitric oxide (NO) dependent vasodilatation as well as enhanced pro-thrombotic and pro-inflammatory properties (Hink et al., 2001; Davignon and Ganz, 2004; Hartge et al., 2007). Endothelial dysfunction is a well established precursor of atherosclerosis, particularly in the setting of diabetes (Schalkwijk and Stehouwer, 2005). The diabetes-associated factors that impair normal endothelial function include increased synthesis of vasoconstrictors such as angiotensin II (Ang II) and endothelin-1, uncoupling of endothelial nitric oxide synthase (eNOS; leading to reduced bioavailability of NO), and increased expression and activity of ROS-producing enzymes (such as NADPH oxidases, Nox) which trigger the expression of adhesion and chemotactic molecules that promote the recruitment of inflammatory cells to the arterial wall (Figure 1) (Hink et al., 2001; Guzik et al., 2002; Lüscher et al., 2003; Hartge et al., 2007). Aortic lesions of diabetic ApoE knockout (KO) mice show increased gene expression of pro-inflammatory molecules MCP-1, VCAM-1, and NF-κB subunit p65 associated with increased pro-atherogenic cellularity [macrophages, T cells, and smooth muscle cells (SMCs)] compared to non-diabetic controls (Soro-Paavonen et al., 2008). In line with these in vivo findings, human endothelial cells exposed to high glucose conditions show increased leukocyte binding associated with increased expression of E-selectin, ICAM-1, VCAM-1, and MCP-1 through activation of NF-κB (Kim et al., 1994; Morigi et al., 1998; Piga et al., 2007). In addition, recent studies have revealed a striking association between glucose-induced endothelial expression of adhesion molecules VCAM-1 and P-selectin as well as the chemokines MCP-1 and fractalkine with Nox-derived ROS production (Manduteanu et al., 2010; Gray et al., 2013). These data indicate that diabetes-associated hyperglycemia and oxidative stress promote leukocyte-endothelial cell interactions required for the recruitment of leukocytes to the inflamed vessel.

Bottom Line: We aim to describe the interaction between advanced glycation end products and their principle receptor RAGE, angiotensin II, and the Ang II type 1 receptor, in addition to reactive oxygen species (ROS) production by NADPH-oxidase enzymes that are relevant to vascular and immune cell function in the context of diabetic vasculopathy.Furthermore, we will touch on recent advances in epigenetic medicine that have revealed high glucose-mediated changes in the transcription of genes with known pro-inflammatory downstream targets.Finally, novel anti-atherosclerosis strategies that target the vascular immune interface will be explored; such as vaccination against modified low-density lipoprotein and pharmacological inhibition of ROS-producing enzymes.

View Article: PubMed Central - PubMed

Affiliation: Baker IDI Heart and Diabetes Research Institute , Melbourne, VIC , Australia ; Department of Medicine, Monash University , Melbourne, VIC , Australia.

ABSTRACT
A central mechanism driving vascular disease in diabetes is immune cell-mediated inflammation. In diabetes, enhanced oxidation and glycation of macromolecules, such as lipoproteins, insults the endothelium, and activates both innate and adaptive arms of the immune system by generating new antigens for presentation to adaptive immune cells. Chronic inflammation of the endothelium in diabetes leads to continuous infiltration and accumulation of leukocytes at sites of endothelial cell injury. We will describe the central role of the macrophage as a source of signaling molecules and damaging by-products which activate infiltrating lymphocytes in the tissue and contribute to the pro-oxidant and pro-inflammatory microenvironment. An important aspect to be considered is the diabetes-associated defects in the immune system, such as fewer or dysfunctional athero-protective leukocyte subsets in the diabetic lesion compared to non-diabetic lesions. This review will discuss the key pro-inflammatory signaling pathways responsible for leukocyte recruitment and activation in the injured vessel, with particular focus on pro- and anti-inflammatory pathways aberrantly activated or repressed in diabetes. We aim to describe the interaction between advanced glycation end products and their principle receptor RAGE, angiotensin II, and the Ang II type 1 receptor, in addition to reactive oxygen species (ROS) production by NADPH-oxidase enzymes that are relevant to vascular and immune cell function in the context of diabetic vasculopathy. Furthermore, we will touch on recent advances in epigenetic medicine that have revealed high glucose-mediated changes in the transcription of genes with known pro-inflammatory downstream targets. Finally, novel anti-atherosclerosis strategies that target the vascular immune interface will be explored; such as vaccination against modified low-density lipoprotein and pharmacological inhibition of ROS-producing enzymes.

No MeSH data available.


Related in: MedlinePlus