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Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1–induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1's ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging.
Keywords: IGF-1, Oxidant stress, Aging, Atherosclerosis, Inflammation
IT is widely accepted that aging is an important risk factor for the development of atherosclerosis and its vascular complications. The underlying mechanism whereby aging elevates the probability of disease onset remains obscure; however, it is likely closely related to underlying mechanisms of atherogenesis, the most accepted being the oxidation hypothesis (1). In brief, oxidatively modified lipoproteins cause lipid-laden macrophage, or foam cell, accumulation in the fatty streak, leading to the initiation of atherosclerotic lesion formation. Subsequent recruitment of immune cells establishes a proinflammatory status, further causing elevated oxidative stress, which in turn triggers a series of events including apoptotic or necrotic death of vascular and nonvascular cells. Endothelial dysfunction, commonly represented by dysregulation of the normal contractile response of the vasculature, contributes to the recruitment of immune cells and the proinflammatory status. Oxidative stress induced lesion formation and endothelial dysfunction are interrelated, that is, an elevation in oxidative stress promotes endothelial dysfunction, and vice versa, endothelial dysfunction promotes atherosclerosis leading to elevated oxidative stress. Intriguingly, increased oxidative stress is also considered to be a key factor in mechanisms of aging-associated changes in tissue integrity and function (2). Thus, prooxidant stimuli induce apoptotic and nonapoptotic cell death and premature cell senescence in multiple cell types and tissues, which is highly relevant to both the aging process and to the pathogenesis of atherosclerosis.
Growth Factors and Atherosclerosis; Permissive or Preventative?
Traditionally, the role of growth factors in atherosclerosis has been thought to be permissive, in particular, by stimulating vascular smooth muscle cell (VSMC) migration and proliferation, thereby promoting neointima formation (3–5). However, recent findings from our group and others suggest that some growth factors might have unexpected antiatherogenic effects. Tang and colleagues (8) showed that the absence of platelet-derived growth factor (PDGF)-B in circulating cells, which are a major source of PDGF in atherosclerotic lesions, led to a phenotypic change in lesion composition, namely enhanced inflammatory cell infiltration. Intriguingly, data from the same group indicated that elimination of PDGF-B in circulating cells or blockade of PDGF receptors delayed but did not inhibit smooth muscle accumulation in lesions . Their data suggest a modest contribution of PDGF to atheroprogression but a major inhibitory effect of PDGF on inflammatory responses and on monocyte accumulation, potentially limiting lesion expansion. Recently, cardiac-specific overexpression of transforming growth factor-beta, a growth factor that promotes VSMC proliferation and matrix protein production (reviewed in ), was reported to limit atherosclerotic plaque burden . These plaques were characterized by fewer T-lymphocytes, more collagen, less lipid, and lower expression of inflammatory cytokines (). In our recent study, insulin-like growth factor (IGF)-1 demonstrated antiatherogenic effects via anti-inflammatory and prorepair mechanisms, both of which are mechanisms coupled to changes in vascular oxidative stress . Since prorepair mechanisms and alterations in oxidative stress are also closely related to the physiology of aging, these effects of IGF-1 are relevant to understanding the role of IGF-1 in the aging process. In this review, we will provide a comprehensive update on IGF-1’s ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging.
The IGF-1 System and the Vasculature
IGF-1 has a fundamental role in both prenatal and postnatal development and exerts all of its known physiologic effects by binding to the IGF-1 receptor (IGF-1R) . Its effects are modulated by multiple IGF binding proteins (IGFBPs) . Circulating IGF-1 is generated by the liver under the control of growth hormone (GH). The binding of GH with its hepatic receptor stimulates expression and release of IGF-1 peptide in the circulation, which has high affinity for IGFBPs, and represents the endocrine form of IGF-1 . In addition to the liver, many other organs produce IGF-1, representing autocrine and paracrine forms of IGF-1.
The IGF-1R is a tetramer consisting of two extracellular α-chains and two intracellular β-chains . The β-chains include an intracellular tyrosine kinase domain that is thought to be essential for most of the receptor’s biologic effects . IGF-1R signaling involves autophosphorylation and subsequent tyrosine phosphorylation of Shc and insulin receptor substrate-1, -2, -3, and -4 . Insulin receptor substrate serves as a docking protein and can activate multiple signaling pathways, including phosphoinositide 3-kinase (PI3K), Akt, and mitogen-activated protein kinase . The activation of these signaling pathways induces differential biologic actions of IGF-1, including cell growth, migration, and survival . The IGF-1R can form hybrid receptors with the insulin receptor. These hybrid receptors consist of a half (alpha- and beta-subunits) of the insulin receptor and a half (alpha- and beta- subunits) of the IGF-1R. In VSMCs, both IGF-1 and insulin receptor subunits are expressed, but expression of the former is higher than the latter, resulting in dominant expression of IGF-1R and insulin/IGF-1 hybrid receptors , making VSMCs insensitive to insulin, because the hybrid receptor predominantly mediates IGF-1 signaling .
Clinical Studies Showing a Link Between IGF-1 and CardiovascularDisease
Current studies on the association of IGF-1 levels with cardiovascular disease as an independent cardiovascular risk factor remain inconclusive but suggest an inverse relationship between the prevalence of vascular disease and the bioavailability of IGF-1. Some cross-sectional and prospective studies suggest a positive association between IGF-1 (and in some cases IGFBP-3) and atherosclerosis. Others found that low IGF-1 is a predictor of ischemic heart disease and mortality, consistent with the potential antiapoptotic, antioxidant, and plaque stabilization actions of IGF-1. Several large prospective cohort studies failed to systematically confirm these findings . Several methodological constraints can explain this variance. So far, most studies have used total extractable IGF-1 as an estimate for IGF-1 activity in vivo. However, this provides only a crude estimate of the active hormone, as less than 1% is in its free form, and only free IGF-1 is believed to readily cross the endothelium and interact with its receptor. Of note, IGFBPs, in addition to their potential IGF-1 independent actions, might modulate IGF-1 bioactivity without any changes in the extractable concentrations of total IGF-1. Furthermore, the activity of IGFBPs is modulated by several IGFBP proteases, complicating the analysis of IGF-1 bioactivity. Brugts and colleagues recently introduced a new method to assess IGF-1 bioactivity. Instead of measuring immunoreactive IGF-1, this kinase receptor assay measures IGF-1 bioactivity of serum by its ability to activate IGF-1R autophosphorylation. Thus this assay accounts for IGFBP and IGFBP protease modulation of ligand and receptor interactions. Using this technique, IGF-1 bioactivity was evaluated in relation to survival in a population of elderly men in the Netherlands. Individuals in the highest IGF-bioactivity quartile survived significantly longer than those in the lowest quartile, both in the total population and in subgroups with a high inflammatory risk profile or a medical history of cardiovascular disease. Taken together with results from two other studies that demonstrated an association between low free IGF-1 and risk of carotid and coronary artery disease, these findings suggest that an increase in bioactive IGF-1 is associated with lower atherosclerosis risk and cardiovascular mortality. Further support for this concept comes from studies investigating a polymorphism of the IGF-1 gene promoter, namely a variable length of a cytosine–adenosine repeat sequence, shown to influence circulating IGF-1 levels. In the population-based Rotterdam study , individuals without the wild-type 192 bp allele had 18% lower circulating IGF-1 and were at increased risk for type 2 diabetes, myocardial infarction, and presence of left ventricular hypertrophy . In the presence of hypertension, these individuals also had higher carotid intima-media thickness and higher aortic pulse wave velocity . Additional analyses from this study demonstrated that subjects heterozygous for the 192 bp or 194 bp alleles or noncarriers of these two alleles had lower IGF-1 and higher myocardial infarction-related mortality, particularly in cases of coexisting diabetes . However, others have not replicated these studies and in a study in the United Kingdom, the opposite association was found between the 192 bp allele and IGF-1 levels . It is also relevant to point out that loss-of-function mutations in genes encoding components of the insulin/IGF-1 pathway are associated with extension of life in mice . Recently, mutations in the IGF-1R gene that result in reduced IGF-1 signaling have been identified in centenarians . Additional studies are required to determine whether genetically determined low IGF-1 levels or low bioactivity of IGF-1 is an important risk factor for atherosclerotic burden and a negative determinant of survival.
Life Span, Atherosclerosis, and IGF-1 in Experimental Animal Models
As discussed above, there is evidence that reduced bioavailability of IGF-1 predisposes to development of atherosclerosis, whereas low bioactivity of IGF-1 appears to promote longevity. Considering that atherosclerotic heart disease remains the leading cause of death in the United States, these observations may appear contradictory . However, interpretation of data from cross-sectional studies establishes associations and not causality, and similarly, case-control studies can be confounded by unanticipated factors, for example, identifying appropriate control subjects can be complicated when making a comparison to a group of interest with extreme conditions such as centenarians. Experimental animal models have been useful to study links between aging, IGF-1, and atherosclerosis. Caloric restriction has provided insights into the relation between aging and IGF-1 action. In every reported organism, including yeast, nematode, drosophila, mouse, and rhesus monkey, a reduction in food intake without malnutrition extends life span or delays biological aging and age-related disease onset substantially (for review, see . Because a reduction in food intake decreases signaling activity and/or bioavailability of insulin and IGF-1 (or corresponding orthologs), it has been speculated that diminished insulin and IGF-1 signaling can contribute to longevity. This hypothesis is supported by the reported association between a centenarian age and mutations in the IGF-1R gene, which result in reduced IGF-1 signaling . The premise is also supported by experiments performed in genetically altered models in yeast, nematode, drosophila, and mouse, in which targeting of corresponding orthologs of insulin/IGF-1 effectively elongates life span. For instance, it has been shown that mice with inactivated IGF-1R live on average 26% longer than their wild-type littermates, and these IGF-1R-deficient mice display greater resistance to oxidative stress, a known determinant of ageing . However, the causal role of decreased IGF-1 signaling in caloric restriction-induced extension of murine life span is uncertain. A recent case control study in individuals with a GH receptor deficiency (thus a severe IGF-1 deficiency) did not confirm the life extending effect of low IGF-1 availability . And in an animal model of GH deficiency, caloric restriction and GH/IGF-1 deficiency has been shown to additively increase life span, suggesting their independent effects .
- - - Updated - - -
According to this review it seems that IGF 1 and it's variants could possibly have a protective effect on the heart and vessels. It could possibly have an anti-aging effect on the heart! :cardio:
Keywords:
MC IGF1 LR3
MC IGF1
IGF1
IGF1 LR3
IGF1 protects the heart
IGF 1 anti aging
Keywords: IGF-1, Oxidant stress, Aging, Atherosclerosis, Inflammation
IT is widely accepted that aging is an important risk factor for the development of atherosclerosis and its vascular complications. The underlying mechanism whereby aging elevates the probability of disease onset remains obscure; however, it is likely closely related to underlying mechanisms of atherogenesis, the most accepted being the oxidation hypothesis (1). In brief, oxidatively modified lipoproteins cause lipid-laden macrophage, or foam cell, accumulation in the fatty streak, leading to the initiation of atherosclerotic lesion formation. Subsequent recruitment of immune cells establishes a proinflammatory status, further causing elevated oxidative stress, which in turn triggers a series of events including apoptotic or necrotic death of vascular and nonvascular cells. Endothelial dysfunction, commonly represented by dysregulation of the normal contractile response of the vasculature, contributes to the recruitment of immune cells and the proinflammatory status. Oxidative stress induced lesion formation and endothelial dysfunction are interrelated, that is, an elevation in oxidative stress promotes endothelial dysfunction, and vice versa, endothelial dysfunction promotes atherosclerosis leading to elevated oxidative stress. Intriguingly, increased oxidative stress is also considered to be a key factor in mechanisms of aging-associated changes in tissue integrity and function (2). Thus, prooxidant stimuli induce apoptotic and nonapoptotic cell death and premature cell senescence in multiple cell types and tissues, which is highly relevant to both the aging process and to the pathogenesis of atherosclerosis.
Growth Factors and Atherosclerosis; Permissive or Preventative?
Traditionally, the role of growth factors in atherosclerosis has been thought to be permissive, in particular, by stimulating vascular smooth muscle cell (VSMC) migration and proliferation, thereby promoting neointima formation (3–5). However, recent findings from our group and others suggest that some growth factors might have unexpected antiatherogenic effects. Tang and colleagues (8) showed that the absence of platelet-derived growth factor (PDGF)-B in circulating cells, which are a major source of PDGF in atherosclerotic lesions, led to a phenotypic change in lesion composition, namely enhanced inflammatory cell infiltration. Intriguingly, data from the same group indicated that elimination of PDGF-B in circulating cells or blockade of PDGF receptors delayed but did not inhibit smooth muscle accumulation in lesions . Their data suggest a modest contribution of PDGF to atheroprogression but a major inhibitory effect of PDGF on inflammatory responses and on monocyte accumulation, potentially limiting lesion expansion. Recently, cardiac-specific overexpression of transforming growth factor-beta, a growth factor that promotes VSMC proliferation and matrix protein production (reviewed in ), was reported to limit atherosclerotic plaque burden . These plaques were characterized by fewer T-lymphocytes, more collagen, less lipid, and lower expression of inflammatory cytokines (). In our recent study, insulin-like growth factor (IGF)-1 demonstrated antiatherogenic effects via anti-inflammatory and prorepair mechanisms, both of which are mechanisms coupled to changes in vascular oxidative stress . Since prorepair mechanisms and alterations in oxidative stress are also closely related to the physiology of aging, these effects of IGF-1 are relevant to understanding the role of IGF-1 in the aging process. In this review, we will provide a comprehensive update on IGF-1’s ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging.
The IGF-1 System and the Vasculature
IGF-1 has a fundamental role in both prenatal and postnatal development and exerts all of its known physiologic effects by binding to the IGF-1 receptor (IGF-1R) . Its effects are modulated by multiple IGF binding proteins (IGFBPs) . Circulating IGF-1 is generated by the liver under the control of growth hormone (GH). The binding of GH with its hepatic receptor stimulates expression and release of IGF-1 peptide in the circulation, which has high affinity for IGFBPs, and represents the endocrine form of IGF-1 . In addition to the liver, many other organs produce IGF-1, representing autocrine and paracrine forms of IGF-1.
The IGF-1R is a tetramer consisting of two extracellular α-chains and two intracellular β-chains . The β-chains include an intracellular tyrosine kinase domain that is thought to be essential for most of the receptor’s biologic effects . IGF-1R signaling involves autophosphorylation and subsequent tyrosine phosphorylation of Shc and insulin receptor substrate-1, -2, -3, and -4 . Insulin receptor substrate serves as a docking protein and can activate multiple signaling pathways, including phosphoinositide 3-kinase (PI3K), Akt, and mitogen-activated protein kinase . The activation of these signaling pathways induces differential biologic actions of IGF-1, including cell growth, migration, and survival . The IGF-1R can form hybrid receptors with the insulin receptor. These hybrid receptors consist of a half (alpha- and beta-subunits) of the insulin receptor and a half (alpha- and beta- subunits) of the IGF-1R. In VSMCs, both IGF-1 and insulin receptor subunits are expressed, but expression of the former is higher than the latter, resulting in dominant expression of IGF-1R and insulin/IGF-1 hybrid receptors , making VSMCs insensitive to insulin, because the hybrid receptor predominantly mediates IGF-1 signaling .
Clinical Studies Showing a Link Between IGF-1 and CardiovascularDisease
Current studies on the association of IGF-1 levels with cardiovascular disease as an independent cardiovascular risk factor remain inconclusive but suggest an inverse relationship between the prevalence of vascular disease and the bioavailability of IGF-1. Some cross-sectional and prospective studies suggest a positive association between IGF-1 (and in some cases IGFBP-3) and atherosclerosis. Others found that low IGF-1 is a predictor of ischemic heart disease and mortality, consistent with the potential antiapoptotic, antioxidant, and plaque stabilization actions of IGF-1. Several large prospective cohort studies failed to systematically confirm these findings . Several methodological constraints can explain this variance. So far, most studies have used total extractable IGF-1 as an estimate for IGF-1 activity in vivo. However, this provides only a crude estimate of the active hormone, as less than 1% is in its free form, and only free IGF-1 is believed to readily cross the endothelium and interact with its receptor. Of note, IGFBPs, in addition to their potential IGF-1 independent actions, might modulate IGF-1 bioactivity without any changes in the extractable concentrations of total IGF-1. Furthermore, the activity of IGFBPs is modulated by several IGFBP proteases, complicating the analysis of IGF-1 bioactivity. Brugts and colleagues recently introduced a new method to assess IGF-1 bioactivity. Instead of measuring immunoreactive IGF-1, this kinase receptor assay measures IGF-1 bioactivity of serum by its ability to activate IGF-1R autophosphorylation. Thus this assay accounts for IGFBP and IGFBP protease modulation of ligand and receptor interactions. Using this technique, IGF-1 bioactivity was evaluated in relation to survival in a population of elderly men in the Netherlands. Individuals in the highest IGF-bioactivity quartile survived significantly longer than those in the lowest quartile, both in the total population and in subgroups with a high inflammatory risk profile or a medical history of cardiovascular disease. Taken together with results from two other studies that demonstrated an association between low free IGF-1 and risk of carotid and coronary artery disease, these findings suggest that an increase in bioactive IGF-1 is associated with lower atherosclerosis risk and cardiovascular mortality. Further support for this concept comes from studies investigating a polymorphism of the IGF-1 gene promoter, namely a variable length of a cytosine–adenosine repeat sequence, shown to influence circulating IGF-1 levels. In the population-based Rotterdam study , individuals without the wild-type 192 bp allele had 18% lower circulating IGF-1 and were at increased risk for type 2 diabetes, myocardial infarction, and presence of left ventricular hypertrophy . In the presence of hypertension, these individuals also had higher carotid intima-media thickness and higher aortic pulse wave velocity . Additional analyses from this study demonstrated that subjects heterozygous for the 192 bp or 194 bp alleles or noncarriers of these two alleles had lower IGF-1 and higher myocardial infarction-related mortality, particularly in cases of coexisting diabetes . However, others have not replicated these studies and in a study in the United Kingdom, the opposite association was found between the 192 bp allele and IGF-1 levels . It is also relevant to point out that loss-of-function mutations in genes encoding components of the insulin/IGF-1 pathway are associated with extension of life in mice . Recently, mutations in the IGF-1R gene that result in reduced IGF-1 signaling have been identified in centenarians . Additional studies are required to determine whether genetically determined low IGF-1 levels or low bioactivity of IGF-1 is an important risk factor for atherosclerotic burden and a negative determinant of survival.
Life Span, Atherosclerosis, and IGF-1 in Experimental Animal Models
As discussed above, there is evidence that reduced bioavailability of IGF-1 predisposes to development of atherosclerosis, whereas low bioactivity of IGF-1 appears to promote longevity. Considering that atherosclerotic heart disease remains the leading cause of death in the United States, these observations may appear contradictory . However, interpretation of data from cross-sectional studies establishes associations and not causality, and similarly, case-control studies can be confounded by unanticipated factors, for example, identifying appropriate control subjects can be complicated when making a comparison to a group of interest with extreme conditions such as centenarians. Experimental animal models have been useful to study links between aging, IGF-1, and atherosclerosis. Caloric restriction has provided insights into the relation between aging and IGF-1 action. In every reported organism, including yeast, nematode, drosophila, mouse, and rhesus monkey, a reduction in food intake without malnutrition extends life span or delays biological aging and age-related disease onset substantially (for review, see . Because a reduction in food intake decreases signaling activity and/or bioavailability of insulin and IGF-1 (or corresponding orthologs), it has been speculated that diminished insulin and IGF-1 signaling can contribute to longevity. This hypothesis is supported by the reported association between a centenarian age and mutations in the IGF-1R gene, which result in reduced IGF-1 signaling . The premise is also supported by experiments performed in genetically altered models in yeast, nematode, drosophila, and mouse, in which targeting of corresponding orthologs of insulin/IGF-1 effectively elongates life span. For instance, it has been shown that mice with inactivated IGF-1R live on average 26% longer than their wild-type littermates, and these IGF-1R-deficient mice display greater resistance to oxidative stress, a known determinant of ageing . However, the causal role of decreased IGF-1 signaling in caloric restriction-induced extension of murine life span is uncertain. A recent case control study in individuals with a GH receptor deficiency (thus a severe IGF-1 deficiency) did not confirm the life extending effect of low IGF-1 availability . And in an animal model of GH deficiency, caloric restriction and GH/IGF-1 deficiency has been shown to additively increase life span, suggesting their independent effects .
- - - Updated - - -
According to this review it seems that IGF 1 and it's variants could possibly have a protective effect on the heart and vessels. It could possibly have an anti-aging effect on the heart! :cardio:
Keywords:
MC IGF1 LR3
MC IGF1
IGF1
IGF1 LR3
IGF1 protects the heart
IGF 1 anti aging
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