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Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling.

Chistiakov DA, Sobenin IA, Orekhov AN, Bobryshev YV - Biomed Res Int (2015)

Bottom Line: A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs).In contrast, these miRNAs stimulate VSMCs and switching from the VSMC "contractile" phenotype to the "synthetic" phenotype associated with induction of proliferation and motility.In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Nanobiotechnology, Pirogov Russian State Medical University, Moscow 117997, Russia ; The Mount Sinai Community Clinical Oncology Program, Mount Sinai Comprehensive Cancer Center, Mount Sinai Medical Center, Miami Beach, FL 33140, USA.

ABSTRACT
A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). These miRNAs contribute to vascular remodeling, an adaptive process involving phenotypic and behavioral changes in vascular cells in response to vascular injury. In proliferative vascular diseases such as atherosclerosis, pathological vascular remodeling plays a prominent role. The miR-221/222 cluster controls development and differentiation of ECs but inhibits their proangiogenic activation, proliferation, and migration. miR-221/222 are primarily implicated in maintaining endothelial integrity and supporting quiescent EC phenotype. Vascular expression of miR-221/222 is upregulated in initial atherogenic stages causing inhibition of angiogenic recruitment of ECs and increasing endothelial dysfunction and EC apoptosis. In contrast, these miRNAs stimulate VSMCs and switching from the VSMC "contractile" phenotype to the "synthetic" phenotype associated with induction of proliferation and motility. In atherosclerotic vessels, miR-221/222 drive neointima formation. Both miRNAs contribute to atherogenic calcification of VSMCs. In advanced plaques, chronic inflammation downregulates miR-221/222 expression in ECs that in turn could activate intralesion neoangiogenesis. In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles.

No MeSH data available.


Related in: MedlinePlus

Effects of miR-221/222 on vascular endothelium and vascular smooth muscle cells (VSMCs) in atherosclerotic vascular remodeling. In arterial endothelial cells (ECs), expression of miR-221/222 could be upregulated by angiotensin II and shear stress. miR-221/222 are able to positively regulate expression through suppression of RAS p21 protein activator 1 (RASA1), an inhibitor of CREB (cAMP response element-binding protein) that drives angiotensin II induced expression of both miRNAs. Increased levels of miR-221/222 suppress angiogenic activation of quiescent terminally differentiated ECs through inhibiting endothelial proliferation and migration. Proliferation is suppressed via negative regulatory effects of the miR-221/222 cluster on several key genes such as cyclin-dependent kinase cell cycle regulators p21Cip1 and p27Kip1, transcription factors Ets1 and Ets2, signal transducer and activator STAT5a, and receptor for mast/stem cell growth factor c-kit. Notably, miR-221/222 downregulate expression of endothelial NO-synthase (eNOS) that lead to lowered production of nitric oxide (NO), an important modulator of function and proliferation of vascular ECs. Decreased NO production contributes to endothelial dysfunction and promotes EC senescence. miR-221/222 could downregulate p21Cip1 either directly or through blocking of ZEB2 (zinc finger E-box binding homeobox 2), which represses translation of mesenchyme homeobox 2 (MEOX2 or GAX), a transcriptional activator of p21Cip1. The miR-221/222 cluster attenuates EC migration by suppressing endothelial production of matrix metalloproteinases (MMPs) and several key adhesion modulators such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), integrin-β3, and serine/threonine-protein kinase PAK-1. The miR-221/222 cluster could probably diminish endothelial expression of adiponectin receptor AdipoR1. Adiponectin is produced by adipocytes and plays protective role for ECs by preventing endothelial dysfunction. In obesity, miR-221/222 are upregulated in the adipose tissue causing activation of lipid catabolism (lipolysis and fatty cell oxidation) through inhibition of Ets1, a transcription factor that controls expression of fatty acid synthase and other lipid-synthesizing enzymes. As a result, adipocytes release increased amounts of free fatty acids to blood that inhibit insulin signaling in liver and skeletal muscle inducing peripheral insulin resistance. Insulin resistance contributes to endothelial dysfunction. In VSMCs, expression of miR-221/222 is stimulated by angiotensin II and platelet-derived growth factor (PDGF) that is secreted by activated platelets and ECs in response to vascular injury. Upregulation of these miRNAs supports proliferation and increase mobility of VSMCs. In VSMCs, miR-221/222 inhibit several regulatory factors such as those of p21Cip1, p27Kip1, p57Kip2, c-kit, and phosphatase and tensin homolog (PTEN) that are crucial for differentiation and establishment of the contractile phenotype of VSMCs. p57Kip2 and c-kit activate MyoD and myocardin, two key transcription factors involved in myogenesis. Indeed, miR-221/222-dependent downregulation of expression of SMC-specific contractile proteins causes VSMC dedifferentiation and switch from the “contractile” to “synthetic” phenotype. By suppressing PTEN, miR-221/222 induce expression of several proinflammatory chemokines such as monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor 1α (SDF-1α) that attract proinflammatory lymphocytes, dendritic cells, and macrophages to the inflamed site, for example, to the atherosclerotic plaque. In addition, miR-221/222 downregulate PUMA (p53 upregulated modulator of apoptosis), a critical apoptotic inducer thereby preventing apoptosis of VSMCs. Finally, dedifferentiated VSMCs become involved in neointima formation, an essential stage in atherosclerosis-associated remodeling of the arterial wall.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4499635&req=5

fig2: Effects of miR-221/222 on vascular endothelium and vascular smooth muscle cells (VSMCs) in atherosclerotic vascular remodeling. In arterial endothelial cells (ECs), expression of miR-221/222 could be upregulated by angiotensin II and shear stress. miR-221/222 are able to positively regulate expression through suppression of RAS p21 protein activator 1 (RASA1), an inhibitor of CREB (cAMP response element-binding protein) that drives angiotensin II induced expression of both miRNAs. Increased levels of miR-221/222 suppress angiogenic activation of quiescent terminally differentiated ECs through inhibiting endothelial proliferation and migration. Proliferation is suppressed via negative regulatory effects of the miR-221/222 cluster on several key genes such as cyclin-dependent kinase cell cycle regulators p21Cip1 and p27Kip1, transcription factors Ets1 and Ets2, signal transducer and activator STAT5a, and receptor for mast/stem cell growth factor c-kit. Notably, miR-221/222 downregulate expression of endothelial NO-synthase (eNOS) that lead to lowered production of nitric oxide (NO), an important modulator of function and proliferation of vascular ECs. Decreased NO production contributes to endothelial dysfunction and promotes EC senescence. miR-221/222 could downregulate p21Cip1 either directly or through blocking of ZEB2 (zinc finger E-box binding homeobox 2), which represses translation of mesenchyme homeobox 2 (MEOX2 or GAX), a transcriptional activator of p21Cip1. The miR-221/222 cluster attenuates EC migration by suppressing endothelial production of matrix metalloproteinases (MMPs) and several key adhesion modulators such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), integrin-β3, and serine/threonine-protein kinase PAK-1. The miR-221/222 cluster could probably diminish endothelial expression of adiponectin receptor AdipoR1. Adiponectin is produced by adipocytes and plays protective role for ECs by preventing endothelial dysfunction. In obesity, miR-221/222 are upregulated in the adipose tissue causing activation of lipid catabolism (lipolysis and fatty cell oxidation) through inhibition of Ets1, a transcription factor that controls expression of fatty acid synthase and other lipid-synthesizing enzymes. As a result, adipocytes release increased amounts of free fatty acids to blood that inhibit insulin signaling in liver and skeletal muscle inducing peripheral insulin resistance. Insulin resistance contributes to endothelial dysfunction. In VSMCs, expression of miR-221/222 is stimulated by angiotensin II and platelet-derived growth factor (PDGF) that is secreted by activated platelets and ECs in response to vascular injury. Upregulation of these miRNAs supports proliferation and increase mobility of VSMCs. In VSMCs, miR-221/222 inhibit several regulatory factors such as those of p21Cip1, p27Kip1, p57Kip2, c-kit, and phosphatase and tensin homolog (PTEN) that are crucial for differentiation and establishment of the contractile phenotype of VSMCs. p57Kip2 and c-kit activate MyoD and myocardin, two key transcription factors involved in myogenesis. Indeed, miR-221/222-dependent downregulation of expression of SMC-specific contractile proteins causes VSMC dedifferentiation and switch from the “contractile” to “synthetic” phenotype. By suppressing PTEN, miR-221/222 induce expression of several proinflammatory chemokines such as monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor 1α (SDF-1α) that attract proinflammatory lymphocytes, dendritic cells, and macrophages to the inflamed site, for example, to the atherosclerotic plaque. In addition, miR-221/222 downregulate PUMA (p53 upregulated modulator of apoptosis), a critical apoptotic inducer thereby preventing apoptosis of VSMCs. Finally, dedifferentiated VSMCs become involved in neointima formation, an essential stage in atherosclerosis-associated remodeling of the arterial wall.

Mentions: In EPCs, miR-221 was found to suppress serine/threonine-protein kinase PAK1 [70] (Figure 2). PAK1 belongs to the family of p21Waf1/Cip1-activated kinases and serves as a target for small GTPases Cdc42 and Rac [71]. EPCs are known to play an essential role in vascular repair and maintenance of vascular homeostasis through reendothelialization and neovascularization. EPCs transfected with miR-221/miR-222 loose capacity to do wound healing and tube formation [63].


Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling.

Chistiakov DA, Sobenin IA, Orekhov AN, Bobryshev YV - Biomed Res Int (2015)

Effects of miR-221/222 on vascular endothelium and vascular smooth muscle cells (VSMCs) in atherosclerotic vascular remodeling. In arterial endothelial cells (ECs), expression of miR-221/222 could be upregulated by angiotensin II and shear stress. miR-221/222 are able to positively regulate expression through suppression of RAS p21 protein activator 1 (RASA1), an inhibitor of CREB (cAMP response element-binding protein) that drives angiotensin II induced expression of both miRNAs. Increased levels of miR-221/222 suppress angiogenic activation of quiescent terminally differentiated ECs through inhibiting endothelial proliferation and migration. Proliferation is suppressed via negative regulatory effects of the miR-221/222 cluster on several key genes such as cyclin-dependent kinase cell cycle regulators p21Cip1 and p27Kip1, transcription factors Ets1 and Ets2, signal transducer and activator STAT5a, and receptor for mast/stem cell growth factor c-kit. Notably, miR-221/222 downregulate expression of endothelial NO-synthase (eNOS) that lead to lowered production of nitric oxide (NO), an important modulator of function and proliferation of vascular ECs. Decreased NO production contributes to endothelial dysfunction and promotes EC senescence. miR-221/222 could downregulate p21Cip1 either directly or through blocking of ZEB2 (zinc finger E-box binding homeobox 2), which represses translation of mesenchyme homeobox 2 (MEOX2 or GAX), a transcriptional activator of p21Cip1. The miR-221/222 cluster attenuates EC migration by suppressing endothelial production of matrix metalloproteinases (MMPs) and several key adhesion modulators such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), integrin-β3, and serine/threonine-protein kinase PAK-1. The miR-221/222 cluster could probably diminish endothelial expression of adiponectin receptor AdipoR1. Adiponectin is produced by adipocytes and plays protective role for ECs by preventing endothelial dysfunction. In obesity, miR-221/222 are upregulated in the adipose tissue causing activation of lipid catabolism (lipolysis and fatty cell oxidation) through inhibition of Ets1, a transcription factor that controls expression of fatty acid synthase and other lipid-synthesizing enzymes. As a result, adipocytes release increased amounts of free fatty acids to blood that inhibit insulin signaling in liver and skeletal muscle inducing peripheral insulin resistance. Insulin resistance contributes to endothelial dysfunction. In VSMCs, expression of miR-221/222 is stimulated by angiotensin II and platelet-derived growth factor (PDGF) that is secreted by activated platelets and ECs in response to vascular injury. Upregulation of these miRNAs supports proliferation and increase mobility of VSMCs. In VSMCs, miR-221/222 inhibit several regulatory factors such as those of p21Cip1, p27Kip1, p57Kip2, c-kit, and phosphatase and tensin homolog (PTEN) that are crucial for differentiation and establishment of the contractile phenotype of VSMCs. p57Kip2 and c-kit activate MyoD and myocardin, two key transcription factors involved in myogenesis. Indeed, miR-221/222-dependent downregulation of expression of SMC-specific contractile proteins causes VSMC dedifferentiation and switch from the “contractile” to “synthetic” phenotype. By suppressing PTEN, miR-221/222 induce expression of several proinflammatory chemokines such as monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor 1α (SDF-1α) that attract proinflammatory lymphocytes, dendritic cells, and macrophages to the inflamed site, for example, to the atherosclerotic plaque. In addition, miR-221/222 downregulate PUMA (p53 upregulated modulator of apoptosis), a critical apoptotic inducer thereby preventing apoptosis of VSMCs. Finally, dedifferentiated VSMCs become involved in neointima formation, an essential stage in atherosclerosis-associated remodeling of the arterial wall.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4499635&req=5

fig2: Effects of miR-221/222 on vascular endothelium and vascular smooth muscle cells (VSMCs) in atherosclerotic vascular remodeling. In arterial endothelial cells (ECs), expression of miR-221/222 could be upregulated by angiotensin II and shear stress. miR-221/222 are able to positively regulate expression through suppression of RAS p21 protein activator 1 (RASA1), an inhibitor of CREB (cAMP response element-binding protein) that drives angiotensin II induced expression of both miRNAs. Increased levels of miR-221/222 suppress angiogenic activation of quiescent terminally differentiated ECs through inhibiting endothelial proliferation and migration. Proliferation is suppressed via negative regulatory effects of the miR-221/222 cluster on several key genes such as cyclin-dependent kinase cell cycle regulators p21Cip1 and p27Kip1, transcription factors Ets1 and Ets2, signal transducer and activator STAT5a, and receptor for mast/stem cell growth factor c-kit. Notably, miR-221/222 downregulate expression of endothelial NO-synthase (eNOS) that lead to lowered production of nitric oxide (NO), an important modulator of function and proliferation of vascular ECs. Decreased NO production contributes to endothelial dysfunction and promotes EC senescence. miR-221/222 could downregulate p21Cip1 either directly or through blocking of ZEB2 (zinc finger E-box binding homeobox 2), which represses translation of mesenchyme homeobox 2 (MEOX2 or GAX), a transcriptional activator of p21Cip1. The miR-221/222 cluster attenuates EC migration by suppressing endothelial production of matrix metalloproteinases (MMPs) and several key adhesion modulators such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), integrin-β3, and serine/threonine-protein kinase PAK-1. The miR-221/222 cluster could probably diminish endothelial expression of adiponectin receptor AdipoR1. Adiponectin is produced by adipocytes and plays protective role for ECs by preventing endothelial dysfunction. In obesity, miR-221/222 are upregulated in the adipose tissue causing activation of lipid catabolism (lipolysis and fatty cell oxidation) through inhibition of Ets1, a transcription factor that controls expression of fatty acid synthase and other lipid-synthesizing enzymes. As a result, adipocytes release increased amounts of free fatty acids to blood that inhibit insulin signaling in liver and skeletal muscle inducing peripheral insulin resistance. Insulin resistance contributes to endothelial dysfunction. In VSMCs, expression of miR-221/222 is stimulated by angiotensin II and platelet-derived growth factor (PDGF) that is secreted by activated platelets and ECs in response to vascular injury. Upregulation of these miRNAs supports proliferation and increase mobility of VSMCs. In VSMCs, miR-221/222 inhibit several regulatory factors such as those of p21Cip1, p27Kip1, p57Kip2, c-kit, and phosphatase and tensin homolog (PTEN) that are crucial for differentiation and establishment of the contractile phenotype of VSMCs. p57Kip2 and c-kit activate MyoD and myocardin, two key transcription factors involved in myogenesis. Indeed, miR-221/222-dependent downregulation of expression of SMC-specific contractile proteins causes VSMC dedifferentiation and switch from the “contractile” to “synthetic” phenotype. By suppressing PTEN, miR-221/222 induce expression of several proinflammatory chemokines such as monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor 1α (SDF-1α) that attract proinflammatory lymphocytes, dendritic cells, and macrophages to the inflamed site, for example, to the atherosclerotic plaque. In addition, miR-221/222 downregulate PUMA (p53 upregulated modulator of apoptosis), a critical apoptotic inducer thereby preventing apoptosis of VSMCs. Finally, dedifferentiated VSMCs become involved in neointima formation, an essential stage in atherosclerosis-associated remodeling of the arterial wall.
Mentions: In EPCs, miR-221 was found to suppress serine/threonine-protein kinase PAK1 [70] (Figure 2). PAK1 belongs to the family of p21Waf1/Cip1-activated kinases and serves as a target for small GTPases Cdc42 and Rac [71]. EPCs are known to play an essential role in vascular repair and maintenance of vascular homeostasis through reendothelialization and neovascularization. EPCs transfected with miR-221/miR-222 loose capacity to do wound healing and tube formation [63].

Bottom Line: A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs).In contrast, these miRNAs stimulate VSMCs and switching from the VSMC "contractile" phenotype to the "synthetic" phenotype associated with induction of proliferation and motility.In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Nanobiotechnology, Pirogov Russian State Medical University, Moscow 117997, Russia ; The Mount Sinai Community Clinical Oncology Program, Mount Sinai Comprehensive Cancer Center, Mount Sinai Medical Center, Miami Beach, FL 33140, USA.

ABSTRACT
A cluster of miR-221/222 is a key player in vascular biology through exhibiting its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). These miRNAs contribute to vascular remodeling, an adaptive process involving phenotypic and behavioral changes in vascular cells in response to vascular injury. In proliferative vascular diseases such as atherosclerosis, pathological vascular remodeling plays a prominent role. The miR-221/222 cluster controls development and differentiation of ECs but inhibits their proangiogenic activation, proliferation, and migration. miR-221/222 are primarily implicated in maintaining endothelial integrity and supporting quiescent EC phenotype. Vascular expression of miR-221/222 is upregulated in initial atherogenic stages causing inhibition of angiogenic recruitment of ECs and increasing endothelial dysfunction and EC apoptosis. In contrast, these miRNAs stimulate VSMCs and switching from the VSMC "contractile" phenotype to the "synthetic" phenotype associated with induction of proliferation and motility. In atherosclerotic vessels, miR-221/222 drive neointima formation. Both miRNAs contribute to atherogenic calcification of VSMCs. In advanced plaques, chronic inflammation downregulates miR-221/222 expression in ECs that in turn could activate intralesion neoangiogenesis. In addition, both miRNAs could contribute to cardiovascular pathology through their effects on fat and glucose metabolism in nonvascular tissues such as adipose tissue, liver, and skeletal muscles.

No MeSH data available.


Related in: MedlinePlus