Elastin-Derived Peptides Are New Regulators of Insulin Resistance Development in Mice

Abstract

Although it has long been established that the extracellular matrix acts as a mechanical support, its degradation products, which mainly accumulate during aging, have also been demonstrated to play an important role in cell physiology and the development of cardiovascular and metabolic diseases. In the current study, we show that elastin-derived peptides (EDPs) may be involved in the development of insulin resistance (IRES) in mice. In chow-fed mice, acute or chronic intravenous injections of EDPs induced hyperglycemic effects associated with glucose uptake reduction and IRES in skeletal muscle, liver, and adipose tissue. Based on in vivo, in vitro, and in silico approaches, we propose that this IRES is due to interaction between the insulin receptor (IR) and the neuraminidase-1 subunit of the elastin receptor complex triggered by EDPs. This interplay was correlated with decreased sialic acid levels on the β-chain of the IR and reduction of IR signaling. In conclusion, this is the first study to demonstrate that EDPs, which mainly accumulate with aging, may be involved in the insidious development of IRES.

Obesity-induced remodeling of the adipose tissue elastin network is independent of the metalloelastase MMP-12

“…9,10 In addition to this structural role, elastin-derived peptides have been shown to contribute to insulin resistance by blocking glucose uptake in muscle and adipose tissue. 11 The degradation of the ECM proteins such as collagen and elastin is controlled by proteinases that include matrix metalloproteinases (MMPs) and their endogenous inhibitors such as tissue inhibitors of metalloproteinases (TIMPs). [12][13][14] Of these, MMP-12 is a metalloelastase that has the capacity to degrade elastin and plays important roles in tissue fibrosis and injury.…”

Elastin-Derived Peptides Are New Regulators of Thrombosis

“…29,30 Indeed, ≈29 different peptides were identified in kE mixtures by mass spectrometry analysis with one third containing the bioactive GxxPG motif (not shown). 14 In contrast, the scrambled VVGPGA is unable to adopt the type VIII β-turn conformation because of the lack of GxxPG motif. 30 However, previous studies have reported that simple proline-containing peptides, such as PG, WP, and PGP (putative fragments of collagen and elastin), possess significant antithrombotic and anticoagulant effects in vitro and in vivo.…”

“…These 3 subunits form a functional receptor in human platelets that is able to trigger an increase in sialidase activity on binding to EDP. In contrast to PPCA, the catalytic activity of Neu-1 has been shown to be essential for ERC-mediated effects both in vitro 19,32 and in vivo 13,14 by catalyzing the local conversion of GM 3 ganglioside into lactosylceramide. 19,32 Expression of Neu-1 and PPCA has been already reported in platelets.…”

“…[9][10][11]21,22 A growing body of evidences now suggests that these extracellular matrix degradation products can also affect adjacent/circulating cells and contribute to the progression of age-associated vascular diseases. 21,23 In this context, we recently demonstrated that chronic injection of EDP in mice potentiates atherosclerosis development and promotes insulin resistance, 14,24 2 events that mainly occur during aging. Results are expressed are mean±SEM of 4 to 6 independent experiments, each run in triplicate, and normalized to the control (w/o, without kE).…”

“…This peptide was used at a 4-fold higher concentration than kE (400 μg/mL) because it has been demonstrated that a 4-fold higher concentration is necessary to achieve the equivalent physiological stimulation levels of bioactive elastin peptides released after elastin degradation. 13,14,16 As negative control, a scrambled VVGPGA peptide was used. 17,18 As shown in Figure 2A and 2C, VGVAPG significantly decreased the area covered by platelets from 30 seconds of perfusion.…”