Advanced glycation end products (AGEs) are a group of molecules that are generated through non-enzymatic glycation and accumulate under diabetic condition. The most investigated AGEs precursor is methylglyoxal, a metabolic compound formed mainly from the glycolytic intermediate glyceraldehyde-3-phosphate. Methylglyoxal is more reactive than glucose and shows a stronger ability to cross-link with protein amino groups to form AGEs. Methylglyoxal -induced cytotoxicity may be at least partially responsible for diabetes-related impairments of cardiovascular function. methylglyoxal omeostasis is controlled by the glyoxalase system that consists of two enzymes, glyoxalase 1 (GLO1) and glyoxalase 2. In a recent study, Xue et al. demonstrated that the transcriptional levels of GLO1 are controlled by NF-E2-related factor 2 (Nrf2). The isothiocyanate sulforaphane, derived from the hydrolysis of glucoraphanin abundantly present in broccoli, represents one of the most potent inducers of phase II enzymes through the Keap1–Nrf2 pathway. Aim of this study was to investigate, in primary cultures of rat cardiomyocytes, the biological effects of SF on methylglyoxal-induced cardiotoxicity focusing on the signaling pathways of apoptosis and the modulation of the glyoxalase system. Cell viability was evaluated by MTT assay, caspase 3 activity by a fluorimetric method, ERK1/2, p38 MAPK, JNK and Akt phosphorylation and GLO1 expression by immunoblotting, GLO1 activity spectrophotometrically. We observed that sulforaphane treatment significantly counteracted cell death and apoptosis induced by methylglyoxal, inhibited methylglyoxal induced activation of the pro-apoptotic kinases JNK and p38. Moreover, for the first time, we demonstrated that sulforaphane is able to significantly increase GLO1 protein expression and activity. These findings suggest that targeting the glyoxalase system might be a promising therapeutic strategy to counteract cardiovascular diseases of diabetic patients.
Mechanisms behind sulforaphane cardioprotective effect against methylglyoxal induced citotoxicity
ANGELONI, Cristina;
2012-01-01
Abstract
Advanced glycation end products (AGEs) are a group of molecules that are generated through non-enzymatic glycation and accumulate under diabetic condition. The most investigated AGEs precursor is methylglyoxal, a metabolic compound formed mainly from the glycolytic intermediate glyceraldehyde-3-phosphate. Methylglyoxal is more reactive than glucose and shows a stronger ability to cross-link with protein amino groups to form AGEs. Methylglyoxal -induced cytotoxicity may be at least partially responsible for diabetes-related impairments of cardiovascular function. methylglyoxal omeostasis is controlled by the glyoxalase system that consists of two enzymes, glyoxalase 1 (GLO1) and glyoxalase 2. In a recent study, Xue et al. demonstrated that the transcriptional levels of GLO1 are controlled by NF-E2-related factor 2 (Nrf2). The isothiocyanate sulforaphane, derived from the hydrolysis of glucoraphanin abundantly present in broccoli, represents one of the most potent inducers of phase II enzymes through the Keap1–Nrf2 pathway. Aim of this study was to investigate, in primary cultures of rat cardiomyocytes, the biological effects of SF on methylglyoxal-induced cardiotoxicity focusing on the signaling pathways of apoptosis and the modulation of the glyoxalase system. Cell viability was evaluated by MTT assay, caspase 3 activity by a fluorimetric method, ERK1/2, p38 MAPK, JNK and Akt phosphorylation and GLO1 expression by immunoblotting, GLO1 activity spectrophotometrically. We observed that sulforaphane treatment significantly counteracted cell death and apoptosis induced by methylglyoxal, inhibited methylglyoxal induced activation of the pro-apoptotic kinases JNK and p38. Moreover, for the first time, we demonstrated that sulforaphane is able to significantly increase GLO1 protein expression and activity. These findings suggest that targeting the glyoxalase system might be a promising therapeutic strategy to counteract cardiovascular diseases of diabetic patients.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
