PAPP-A and the IGF system in atherosclerosis: what's up, what's down?

Abstract

Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase with a well-established role in releasing bioactive insulin-like growth factor-1 (IGF-1) from IGF-binding protein-2, -4, and -5 by proteolytic processing of these. The IGF system has repeatedly been suggested to be involved in the pathology of atherosclerosis, and both PAPP-A and IGF-1 are proposed biomarkers and therapeutic targets for this disease. Several experimental approaches based on atherosclerosis mouse models have been undertaken to obtain causative and mechanistic insight to the role of these molecules in atherogenesis. However, reports seem conflicting. The literature suggests that PAPP-A is detrimental, while IGF-1 is beneficial. This raises important questions that need to be addressed. Here we summarize the various studies and discuss potential underlying explanations for this seemingly inconsistency with the objective of better understanding complexities and limitations when manipulating the IGF system in mouse models of atherosclerosis. A debate clarifying what's up and what's down is highly warranted going forward with the ultimate goal of improving atherosclerosis therapy by targeting the IGF system.

Keywords: IGF system; PAPP-A; atherosclerosis; mouse models.

Fig. 1.

Insulin-like growth factor-1 (IGF-1): from secretion to receptor activation. Blue arrows: growth hormone (GH) secreted from the pituitary gland (1) stimulates hepatic IGF-1 secretion into the circulation (2). In turn, IGF-1 reduces GH secretion by negative feedback (3). Yellow arrows: IGF-1 is bound by IGF-binding protein 3 (IGFBP-3) alone or in a ternary complex with IGFBP-3 and acid labile subunit (ALS) (4). Liberated IGF-1 (5) is able to cross the endothelium. Upon entry into the artery interstitium, IGF-1 is met by an IGFBP-4-dominated environment and is bound by IGFBP4 (6). Red arrows: IGF-1 is liberated from IGFBP4 by proteolytic activity of pregnancy-associated plasma protein-A (PAPP-A) (7). PAPP-A is associated with cell surfaces by electrostatic interaction with heparan sulfate glycosaminoglycans (HS-GAGs). IGF-1 is thereby liberated in close proximity to its receptors. Free IGF-1 and IGF-2 and insulin can bind and activate IGF receptor-1 (IGF-1R), insulin receptors (INSR; depending on isotype), and hybrids hereof, while IGF-2 can bind IGF-2R (8). Green arrows: GH can enter the artery wall and stimulate GH receptor (GHR)-expressing cells (e.g., vascular smooth muscle cells (VSMCs) to synthesize IGF-1 (9). IGF-1 produced by local vascular cells (10) is bound by IGFBP-4 and thereby enters the reservoir of PAPP-A-dependent releasable IGF-1 (11).