Intracellular Toxic Advanced Glycation End-Products May Induce Cell Death and Suppress Cardiac Fibroblasts

Abstract

Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) induced by the dysfunction and cell death of cardiomyocytes. Cardiac fibroblasts are activated and differentiate in response to specific signals, such as transforming growth factor-β released from injured cardiomyocytes, and are crucial for the protection of cardiomyocytes, cardiac tissue repair, and remodeling. In contrast, cardiac fibroblasts have been shown to induce injury or death of cardiomyocytes and are implicated in the pathogenesis of diseases such as cardiac hypertrophy. We designated glyceraldehyde-derived advanced glycation end-products (AGEs) as toxic AGEs (TAGE) due to their cytotoxicity and association with LSRD. Intracellular TAGE in cardiomyocytes decreased their beating rate and induced cell death in the absence of myocardial ischemia. The TAGE levels in blood were elevated in patients with CVD and were associated with myocardial ischemia along with increased risk of atherosclerosis in vascular endothelial cells in vitro. The relationships between the dysfunction or cell death of cardiac fibroblasts and intracellular and extracellular TAGE, which are secreted from certain organs, remain unclear. We examined the cytotoxicity of intracellular TAGE by a slot blot analysis, and TAGE-modified bovine serum albumin (TAGE-BSA), a model of extracellular TAGE, in normal human cardiac fibroblasts (HCF). Intracellular TAGE induced cell death in normal HCF, whereas TAGE-BSA did not, even at aberrantly high non-physiological levels. Therefore, only intracellular TAGE induced cell death in HCF under physiological conditions, possibly inhibiting the role of HCF.