Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kα pathway

Abstract

IntroductionVascular damage leads to the rapid recruitment of platelets to the site of injury. Platelets adhere to the newly exposed von Willebrand factor (VWF) and collagen in the extracellular matrix, leading to subsequent platelet activation and the secretion of dense and ␣ granule content into the extracellular media. Platelet granules contain a range of autocrine agonists that can activate or modulate the function of other platelets to form aggregates, including ADP, serotonin, and possibly Gas6 1,2 and tachykinins. 3 Another factor that is found in the ␣ granules in platelets is insulin-like growth factor-1 (IGF-1), 4,5 a growth factor involved in cell proliferation, differentiation, and migration. 6 The presence of IGF-1 at the site of vascular injury is essential in the wound-healing process, 7 and local delivery by platelets may therefore support the healing process.IGF-1 is a peptide hormone whose concentration in plasma increases in response to growth hormone, largely due to increased production by the liver. 8 The effect of IGF-1 is modulated by multiple IGF-binding proteins (IGFBPs), which bind IGF-1 and thereby serve as transporter proteins and storage pools. 6 The receptor for IGF-1 has a wide tissue expression and is closely related to the insulin receptor. The insulin receptor is involved in plasma glucose homeostasis and therefore signals mainly to metabolic responses, whereas the IGF receptor couples primarily to mitogenic responses. Both receptors are heterodimers composed of two ligand-binding ␣ subunits linked by disulphide bridges to two transmembrane ␤ subunits that possess ligand-stimulated tyrosine kinase activity. Ligand binding and subsequent activation leads to the phosphorylation of the major substrates Shc and the insulin receptor substrate (IRS) proteins IRS-1 and IRS-2. Tyrosine phosphorylation of IRS proteins on specific residues creates binding sites for Src homology (SH2)-containing proteins such as the tyrosine phosphatase SHP-2 and the regulatory p85 subunit of phosphoinositide-3 kinase (PI3K), thereby increasing their enzyme activity and/or localizing them to their substrates. Activation of PI3K leads to a rapid rise in PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 , which results in the recruitment of protein kinase B (PKB) to the plasma membrane and subsequent phosphorylation of PKB on Thr308 by PDK1 and Ser473 by second kinase, which is likely to be the mTOR/Rictor complex. 9 Subsequent activation of PKB is involved in numerous cellular responses to insulin and IGF-1. 10,11 Insulin resistance and altered blood IGF-1 levels have been implicated in the development of cardiovascular disease. 12,13 Insulin resistance is described as the reduced ability of insulin to lower glucose concentrations in the blood, and is closely associated with obesity and diabetes. 13 Increased free IGF-1 levels and decreased levels of IGFBP-1 are found in serum of obese subjects compared with lean subjects, whereas total IGF-1 levels are within the normal range. 14 Raised local levels of IGF-1 are also li...

Induction of insulin resistance by the adipokines resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 in human megakaryocytes

“…No leptin effect is seen with platelets, a difference possibly due to the contribution of insulin-like growth factor receptor-1 in these cells. 54 In diabetes-free Aboriginal Canadians high leptin levels at baseline were associated with an increased risk of type 2 diabetes and a similar correlation was found in Japanese men. 36,37 Restistin, PAI-1 and RBP4 also make CHRF-288-11 cells insulin-resistant.…”

Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease–associated thrombosis in mice

“…27,53,54 As reported, Klotho is an endogenous inhibitor of insulin-like growth factor 1 receptor (IGF-1R), whereas IGF-1 can potentiate platelet activation via activating IGF-1R signaling. 27,55 Therefore, the regulation of IGF-1R signaling may be also involved in the inhibitory effect of Klotho on IS-induced platelet activation. Our findings, together with the results of previous studies, demonstrate that there may exist a reciprocal inhibition between IS and Klotho in the pathological process of CKD and its complications.…”

Diabetes and Antiplatelet Therapy in Acute Coronary Syndrome

“…Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 and their subsequent binding with the p85 subunit of phosphoinositide-3 kinase, leading to phosphorylation of protein kinase B, which is involved in several cellular responses to insulin and IGF-1, including modulation of platelet reactivity. 38 Various abnormalities in insulin-mediated signaling have been proposed to be involved in the hampered or abolished platelet-inhibitory effect observed in patients with insulin resistance. 39 Among IRS-dependent factors, insulin resistance provokes an increase in intracellular calcium concentration, leading to enhanced platelet degranulation and aggregation.…”