The Insulin-Like Growth Factor Axis

Abstract

Insulin-like growth factors I and II (IGF-I and -II) and their regulatory proteins are secreted by cells of the cardiovascular system. They are growth promoters for arterial cells and mediators of cardiovascular disease. IGFs are bound to IGF binding proteins (IGFBPs), which modulate IGF ligand-receptor interaction and consequently to IGF action. IGFBPs are in turn posttranslationally modulated by specific proteases. This dynamic balance (IGFs, IGFBPs, and IGFBP proteases) constitutes the IGF axis and ultimately determines the extent of IGF-dependent cellular effects. Dysregulated actions of this axis influence coronary atherosclerosis through effects on vascular smooth muscle cell growth, migration, and extracellular matrix synthesis in the atherosclerotic plaque. IGF-I promotes macrophage chemotaxis, excess LDL cholesterol uptake, and release of proinflammatory cytokines. Endothelial cells also receive the effects of IGFs stimulating their migration and organization forming capillary networks. Neointimal hyperplasia of restenosis after coronary artery injury is also modulated by the IGF axis. IGFs stimulate vascular smooth muscle cell proliferation and migration to form the neointima and upregulate tropoelastin synthesis after disruption of the elastic layer. Understanding IGF axis regulation establishes a scientific basis for strategies directed to limit or reverse plaque growth and vulnerability in atherosclerosis and in the neointimal hyperplasia of restenosis.

Increased IGF1 levels in relation to heart failure and cardiovascular mortality in an elderly population: impact of ACE inhibitors

“…Both low and high levels of circulating IGF1 have been reported to be associated with increased mortality (4)(5)(6) as well as with cardiac failure (7). Protective (1,8,9) as well as harmful (5,10) effects of IGF1 on the CV system have been reported. In adults, IGF1 has anabolic effects on connective tissues, muscles, and heart (11,12).…”

“…It is conceivable that IGF1 plays a dual role in the vascular wall; stimulating nitric oxide (NO) production in the intact endothelium thereby inhibiting smooth muscle cell proliferation, but may directly stimulate smooth muscle cell proliferation if the endothelium is damaged (10,15,16). Angiotensin II is a potent inhibitor of local IGF1 expression, and it has therefore been suggested that angiotensin converting enzyme (ACE) inhibitors may enhance local IGF1 secretion (17).…”

Targeted Expression of a Protease-resistant IGFBP-4 Mutant in Smooth Muscle of Transgenic Mice Results in IGFBP-4 Stabilization and Smooth Muscle Hypotrophy

“…In addition, some IGFBPs bind to components of the extracellular matrix (IGFBP-2, -3, and -5) or the cell membrane (IGFBP-1, -2, -3, and -5), thus providing a mechanism to concentrate IGFs within discrete tissue compartments (2). Free IGFs are released by proteolytic cleavage of the respective IGFBP through the action of specific proteases (3)(4)(5)(6). Proteases that cleave IGFBP-2 (7), IGFBP-3 (8, 9), IGFBP-4 (4 -6), and IGFBP-5 (10 -12) have been reported.…”

“…The protease(s) that cleave IGFBP-4 are found ubiquitously, including the conditioned medium of cultured fibroblasts, decidual cells, osteoblasts, and SMC and in biological fluids such as pregnancy serum and CSF (14, 19 -21). Recently, pregnancy-associated plasma protein-A (PAPP-A) has been identified as a protease for IGFBP-4 (22), and this protein is expressed in smooth muscle cells (3,23).…”

Need and Importance of Biomarkers to Predict Acute Myocardial Infarction and Its Prognosis

“…It has been found to promote repair, thus revealing its role as an inflammation suppressor. 12 Procalcitonin (PCT) is an established biomarker for the diagnosis of sepsis. There is a growing body of evidence that demonstrates that the PCT concentration correlates with the extent of atherosclerosis and prognosis in patients with coronary artery disease (CAD).…”