Objective-Whereas growth factors, via their ability to stimulate vascular smooth muscle cell (VSMC) proliferation and migration, have been thought to play a permissive role in atherosclerosis initiation and progression, the role of insulin-like growth factor-1 (IGF-1) is unknown. Here we report for the first time that IGF-1 infusion decreased atherosclerotic plaque progression in ApoE-deficient mice on a Western diet. Methods and Results-ApoE-null mice (8 weeks) were infused with vehicle or recombinant human IGF-1 and fed a high-fat diet for 12 weeks. Analysis of aortic sinuses revealed that IGF-1 infusion decreased atherosclerotic plaque progression and macrophage infiltration into lesions. Furthermore, IGF-1 decreased vascular expression of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-␣, reduced aortic superoxide formation and urinary 8-isoprostane levels, and increased aortic pAkt and eNOS expression and circulating endothelial progenitor cells, consistent with an antiinflammatory, antioxidant, and prorepair effect on the vasculature. Conclusions-Our data indicate that an increase in circulating IGF-1 reduces vascular inflammatory responses, systemic and vascular oxidant stress and decreases atherosclerotic plaque progression. These findings have major implications for the treatment of atherosclerosis. Key words: insulin-like growth factor Ⅲ atherosclerosis Ⅲ apolipoprotein E Ⅲ inflammatory response Ⅲ oxidative stress A therosclerosis is the principal underlying cause of most cardiovascular disease-related deaths, the leading cause of mortality in the USA. 1 Long considered to result from progressive vascular lipid accumulation, atherosclerosis is now recognized as a chronic inflammatory disease, 2-5 in which oxidative stress plays a key initiating role. Thus, multiple oxidative stimuli including oxidation of low-density lipoprotein (LDL) in the subendothelial space can result in endothelial cell adhesion molecule expression, monocyte and T cell recruitment, and macrophage lipid accumulation and foam cell formation. 6 Growth factors, cytokines, chemokines, and proteases modulate many steps in the atherosclerotic process including the migration and proliferation of smooth muscle cells. Furthermore, vascular and extravascular progenitor cells contribute to atherogenesis, and these include circulating endothelial progenitor cells (EPCs) that are likely part of a vascular repair system. 7 Insulin-like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that is the primary mediator of the effect of growth hormone (GH) on developmental growth. 8 IGF-1 is expressed in vascular cells 9 and in monocyte/macrophages, 10,11 but its role in atherogenesis is unknown. IGF-1 is a mitogen for endothelial cells 12 and vascular smooth muscle cells, 13 and can potentiate endothelial cell TNF-␣-induced c-Jun and NF-B activation. 14 Furthermore, IGF-1 has potent survival effects on vascular cells and prevents oxidized LDL-induced apoptosis of vascular smooth muscle cells. 15 We ha...

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.

Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5′ AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD.