Nonstandard abbreviations used: acetylated LDL (acLDL); insulin receptor (IR); IR substrate 2 (IRS-2); LDL receptor (LDLR); oxidized LDL (oxLDL); scavenger receptor A (SR-A); scavenger receptor BI (SR-BI); Tricine-buffered saline (TBS). Conflict of interest:The authors have declared that no conflict of interest exists. IntroductionThe complications of atherosclerosis in coronary, cerebral, and peripheral arteries are the major reason for hospital admission in diabetics and account for about 80% of the mortality of this condition (1). Although diabetes is often associated with dyslipidemia (2, 3), the excess risk is disproportionate to lipid abnormalities and the root causes of accelerated atherosclerosis in diabetes are not well understood. Some evidence suggests that insulin resistance, commonly seen in overweight individuals with the metabolic syndrome, is an important cause of both diabetes and increased atherosclerosis risk (4). Insulin resistance has been related to dyslipidemia, hypertension, and hypercoagulability, all factors that may promote atherosclerosis (2, 3). Potentially insulin resistance could also be important at the arterial cellular level (5). Defective insulin signaling in endothelial cells leads to impaired NO activity (6), and this is probably proatherogenic. Macrophages also express insulin receptors (IRs) (7), but the relationship of insulin signaling to macrophage foam cell formation has received little attention. Thiazolidinediones, activators of PPAR-γ, have emerged as an important class of drugs in the treatment of type II diabetes. PPAR-γ activators markedly improve insulin resistance and decrease atherosclerosis in mouse models, and may also decrease atherosclerosis in humans (8-11). Although the in vivo mode of action of PPAR-γ activators is not well understood, PPAR-γ is highly expressed in adipocytes and macrophages (11), suggesting these cells could be important targets. Paradoxically, however, PPAR-γ activators increase the expression of the proatherogenic molecule CD36 in cultured macrophages (12). These proatherogenic effects of PPAR-γ activators may be counteracted by an increase in ABCA1, a macrophage transporter that promotes efflux of cholesterol to lipid-poor apolipoproteins, perhaps offsetting increased uptake of modified low-density lipoprotein (LDL) via CD36 (11,13,14). However, the importance of this mechanism is uncertain, and some studies have failed to find any effect of PPAR-γ activators on ABCA1 levels or lipid efflux in macrophages (15, 16).Obese (ob/ob) mice are genetically deficient in leptin and have been widely used as a model of insulin resistance and diabetes (17). In this study, we made the initial observation that macrophages from ob/ob mice have increased uptake of modified LDL, due to post-transcriptional upregulation of CD36 protein. Unexpectedly, the increase in CD36 is caused by defective insulin signaling in macrophages, suggesting that macrophage insulin resistance promotes foam cell formation. Consistent with this hypothesis, in vivo treatment...
The use of targeted therapeutics to replenish pathologically deficient proteins on the luminal endothelial membrane has the potential to revolutionize emergency and cardiovascular medicine. Untargeted recombinant proteins, like activated protein C (APC) and thrombomodulin (TM), have demonstrated beneficial effects in acute vascular disorders, but have failed to have a major impact on clinical care. We recently reported that TM fused with an scFv antibody fragment to platelet endothelial cell adhesion molecule-1 (PECAM-1) exerts therapeutic effects superior to untargeted TM. PECAM-1 is localized to cell-cell junctions, however, whereas the endothelial protein C receptor (EPCR), the key co-factor of TM/APC, is exposed in the apical membrane. Here we tested whether anchoring TM to the intercellular adhesion molecule (ICAM-1) favors scFv/TM collaboration with EPCR. Indeed: i) endothelial targeting scFv/TM to ICAM-1 provides ∼15-fold greater activation of protein C than its PECAM-targeted counterpart; ii) blocking EPCR reduces protein C activation by scFv/TM anchored to endothelial ICAM-1, but not PECAM-1; and iii) anti-ICAM scFv/TM fusion provides more profound anti-inflammatory effects than anti-PECAM scFv/TM in a mouse model of acute lung injury. These findings, obtained using new translational constructs, emphasize the importance of targeting protein therapeutics to the proper surface determinant, in order to optimize their microenvironment and beneficial effects.
Nonstandard abbreviations used: acetylated LDL (acLDL); insulin receptor (IR); IR substrate 2 (IRS-2); LDL receptor (LDLR); oxidized LDL (oxLDL); scavenger receptor A (SR-A); scavenger receptor BI (SR-BI); Tricine-buffered saline (TBS). Conflict of interest:The authors have declared that no conflict of interest exists. IntroductionThe complications of atherosclerosis in coronary, cerebral, and peripheral arteries are the major reason for hospital admission in diabetics and account for about 80% of the mortality of this condition (1). Although diabetes is often associated with dyslipidemia (2, 3), the excess risk is disproportionate to lipid abnormalities and the root causes of accelerated atherosclerosis in diabetes are not well understood. Some evidence suggests that insulin resistance, commonly seen in overweight individuals with the metabolic syndrome, is an important cause of both diabetes and increased atherosclerosis risk (4). Insulin resistance has been related to dyslipidemia, hypertension, and hypercoagulability, all factors that may promote atherosclerosis (2, 3). Potentially insulin resistance could also be important at the arterial cellular level (5). Defective insulin signaling in endothelial cells leads to impaired NO activity (6), and this is probably proatherogenic. Macrophages also express insulin receptors (IRs) (7), but the relationship of insulin signaling to macrophage foam cell formation has received little attention. Thiazolidinediones, activators of PPAR-γ, have emerged as an important class of drugs in the treatment of type II diabetes. PPAR-γ activators markedly improve insulin resistance and decrease atherosclerosis in mouse models, and may also decrease atherosclerosis in humans (8-11). Although the in vivo mode of action of PPAR-γ activators is not well understood, PPAR-γ is highly expressed in adipocytes and macrophages (11), suggesting these cells could be important targets. Paradoxically, however, PPAR-γ activators increase the expression of the proatherogenic molecule CD36 in cultured macrophages (12). These proatherogenic effects of PPAR-γ activators may be counteracted by an increase in ABCA1, a macrophage transporter that promotes efflux of cholesterol to lipid-poor apolipoproteins, perhaps offsetting increased uptake of modified low-density lipoprotein (LDL) via CD36 (11,13,14). However, the importance of this mechanism is uncertain, and some studies have failed to find any effect of PPAR-γ activators on ABCA1 levels or lipid efflux in macrophages (15, 16).Obese (ob/ob) mice are genetically deficient in leptin and have been widely used as a model of insulin resistance and diabetes (17). In this study, we made the initial observation that macrophages from ob/ob mice have increased uptake of modified LDL, due to post-transcriptional upregulation of CD36 protein. Unexpectedly, the increase in CD36 is caused by defective insulin signaling in macrophages, suggesting that macrophage insulin resistance promotes foam cell formation. Consistent with this hypothesis, in vivo treatment...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.