LDL, IGF-1, and VSMC apoptosis: linking atherogenesis to plaque rupture in vulnerable lesions

See article by Gonzales-Timon [12] (pages 247–255) in this issue. Vascular smooth muscle cells (VSMC) play an important role in the sequence of events leading to the formation of atherosclerotic lesions. VSMC that normally reside in the arterial media undergo a series of phenotypic changes and migrate to the arterial intima where they proliferate and secrete extracellular matrix that contributes to the formation of the protective fibrous cap. Eventually these “synthetic” VSMC [1] can undergo apoptosis which is thought to degrade the stability of the plaque and ultimately leads to rupture of the fibrous cap and deposition of thrombus, and thus acute myocardial infarction [2]. Insulin-like growth factor I (IGF-1), a small protein (70 amino acids) secreted by VSMCs and other cells in the vascular wall, appears to stimulate the proliferation of the VSMCs and may also protect these cells from apoptosis [3]. In the early atherogenic period IGF-1 levels are elevated in plaque, but in advanced lesions, the concentrations of this growth factor are substantially diminished [4]. In advanced lesions in humans, this phenomenon appears to result from the loss of IGF-1 receptors from the surface of VSMCs, and this phenomenon increases the probability of apoptotic activity in the VSMCs [5]. It has been well established that atherosclerosis correlates well with the elevation of low-density lipoprotein (LDL) levels in plasma [6,7], and the retention and accumulation of LDL in the atherosclerotic plaque [7,8]. Subsequent oxidation of LDL appears to be responsible for the apoptotic activity in VSMC and eventual plaque rupture [9,10], although the cellular pathways underlying this activity have not been clear. Studies in humans have shown that the progressive development of the atherosclerotic plaque appears to depend on the influx of macrophages, lack of IGF-1, and increased susceptibility of the VSMCs to apoptosis [4]. Similar studies in rats have shown that LDL can increase IGF-1 levels and the levels of IGF-1 receptor in the cells of the atherosclerotic plaque while oxidized LDL tends to decrease levels of IGF-1 and IGF-1 receptor [11]. These findings have led to the hypothesis that once LDL enters the plaque and undergoes oxidation, it can influence the production of IGF-1 by the local VSMCs. In order to further elucidate these questions, the study by Gonzalez-Timon et al. [12] published in this issue of Cardiovascular Research has sought to investigate the effects of LDL on IGF-1 expression in cultured A10 VSMC as well as to investigate the effects of LDL and IGF-1 on the signaling pathways within these cells. The cell line A10 has been shown to have many of the properties of atherosclerotic VSMC [13], and has been used by other investigators to measure the effects of LDL on IGF-1 levels [14]. Elvira Melián et al. [15] previously demonstrated that IGF-1, in the presence of the enzyme phosphatidylinositol 3-kinase, stimulates the proliferation of A10 VSMCs in culture. They also demonstrated that LDL and IGF-1, together with IGF-induced insulin receptor substrate-1 (IRS-1), could stimulate the activity of PI 3-kinase [15]. In the current study by Gonzalez-Timon et al. [12], the influence of native LDL (nLDL) and increasingly oxidized LDL species on the ability of IGF-1 to stimulate proliferation and apoptosis in VSMC was examined. They found that while nLDL increased the ability of IGF-1 to activate VSMC proliferation, oxidized LDL inhibited this process. They also showed that while nLDL had little effect on the anti-apoptotic effects of IGF-1 on VSMCs, oxidized LDL inhibited these effects of IGF-1 as well. When they examined the intracellular signaling pathways that were controlled by IGF-1, such as PI 3-kinase and MAP kinase, they found that oxidized LDL blocked either Akt phosphorylation or PI 3-kinase activity while essentially exerting no effect on ERK-1/2 phosphorylation. This suggested that oxidized LDL could counteract the effects of IGF-1 on cell growth and survival via direct effects on the PI 3-kinase system. This supports the hypothesis that apoptosis of VSMCs results in plaque rupture in vulnerable lesions and may be driven by the decline in IGF-1 activity that occurs in response to the accumulation of oxidized LDL in the plaque. These findings provide a link between the well-established role of increased LDL levels on atherosclerosis progression and the IGF-1 system. It would be of further interest to examine the role of other lipids, e.g., arachidonic acid and ceramide, on these signaling pathways since there is some evidence that these lipids also play a role in apoptosis in VSMCs [16–18].