The Antidiabetic Hormone Glucagon-Like Peptide-1 Induces Formation of New Elastic Fibers in Human Cardiac Fibroblasts After Cross-Activation of IGF-IR

Glucagon-like peptide 1 (GLP-1) is a metabolic hormone involved in the stimulation of insulin biosynthesis and secretion. It has been recently reported that GLP-1 also exerts cardioprotective effects and facilitates functional recovery after myocardial infarction through GLP-1 receptormediated signaling in cardiomyocytes. GLP-1 treatment has been also demonstrated to produce sustained improvement in cardiac function in long-term studies, suggesting the involvement of mechanisms beyond the acute metabolic and cytoprotective effects. For example, the possible interaction of GLP-1 with the cardiac fibroblasts, which are responsible for the postinfarct remodeling and extracellular matrix production, has not been previously explored. Here, we report that cultures of human cardiac fibroblasts treated with GLP-1 peptides display a selective up-regulation in elastin gene expression and a consequent increase in elastic fibers production, in the absence of the classic GLP-1 receptor. Importantly, we provide experimental evidence that this GLP-1-induced elastogenesis is triggered through the cross-activation of the IGF-I receptor. Because GLP-1 does not stimulate deposition of collagen I, nor promote the proliferation or apoptosis of cultured cardiac fibroblasts, we speculate that its elastogenic effect may also contribute to the beneficial remodeling of the human heart after myocardial infarction. (Endocrinology 156: 90 -102, 2015) G lucagon-like peptide 1 (GLP-1) is a hormone synthe- sized and processed in the intestinal L-cells in response to food intake (1). It induces numerous effects in different tissues, including the pancreas, intestines, brain, heart, and kidney after its interaction with the widely expressed classic GLP-1 receptor (GLP-1R) (2). GLP-1 upregulates glucose-dependent insulin secretion and inhibits the release of glucagon, thereby decreasing blood glucose levels and contributing to therapeutic benefits for patients with type 2 diabetes mellitus (3). It is well known that diabetic patients are at an increased risk for coronary heart disease and often have a worse prognosis than nondiabetics after acute myocardial infarction (MI) (4, 5). Intriguingly, clinical (6, 7) and animal studies (8 -15) have shown that both the native GLP-1 (7-36 peptide) and its proteolytic cleavage product, the GLP-1 (9-36 peptide), also contribute to the improvement of ventricular ejection fraction and functional recovery after acute ischemic injury of the heart (10).