TY - JOUR
T1 - D-carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation
AU - Menini, Stefano
AU - Iacobini, Carla
AU - Ricci, Carlo
AU - Scipioni, Angela
AU - Fantauzzi, Claudia Blasetti
AU - Giaccari, Andrea
AU - Salomone, Enrica
AU - Canevotti, Renato
AU - Lapolla, Annunziata
AU - Orioli, Marica
AU - Aldini, Giancarlo
AU - Pugliese, Giuseppe
PY - 2012
Y1 - 2012
N2 - BACKGROUND AND PURPOSE Lipoxidation-derived reactive carbonyl species (RCS) such as 4-hydroxy-2-nonenal (HNE) react with proteins to form advanced lipoxidation end products (ALEs), which have been implicated in both atherosclerosis and renal disease. L-carnosine acts as an endogenous HNE scavenger, but it is rapidly inactivated by carnosinase. This study aimed at assessing the effect of the carnosinase-resistant, D-carnosine, on HNE-induced cellular injury and of its bioavailable prodrug D-carnosine octylester on experimental atherosclerosis and renal disease. EXPERIMENTAL APPROACH Vascular smooth muscle cells (VSMCs) were exposed to HNE or H(2) O(2) plus D-carnosine. ApoE null mice fed a Western, pro-atherogenic diet were treated with D-carnosine octylester for 12 weeks. KEY RESULTS In vitro, D-carnosine attenuated the effect of HNE, but not of H(2) O(2) , on VSMCs. In vivo, D-carnosine octylester-treated mice showed reduced lesion area and a more stable plaque phenotype compared with untreated animals, with reduced foam cell accumulation, inflammation and apoptosis and increased clearance of apoptotic bodies and collagen deposition, resulting in decreased necrotic core formation. Likewise, renal lesions were attenuated in D-carnosine octylester-treated versus untreated mice, with lower inflammation, apoptosis and fibrosis. This was associated with increased urinary levels of HNE-carnosine adducts and reduced protein carbonylation, circulating and tissue ALEs, expression of receptors for these products, and systemic and tissue oxidative stress. CONCLUSIONS AND IMPLICATIONS These data indicate RCS quenching with a D-carnosine ester was highly effective in attenuating experimental atherosclerosis and renal disease by reducing carbonyl stress and inflammation and that this may represent a promising therapeutic strategy in humans.
AB - BACKGROUND AND PURPOSE Lipoxidation-derived reactive carbonyl species (RCS) such as 4-hydroxy-2-nonenal (HNE) react with proteins to form advanced lipoxidation end products (ALEs), which have been implicated in both atherosclerosis and renal disease. L-carnosine acts as an endogenous HNE scavenger, but it is rapidly inactivated by carnosinase. This study aimed at assessing the effect of the carnosinase-resistant, D-carnosine, on HNE-induced cellular injury and of its bioavailable prodrug D-carnosine octylester on experimental atherosclerosis and renal disease. EXPERIMENTAL APPROACH Vascular smooth muscle cells (VSMCs) were exposed to HNE or H(2) O(2) plus D-carnosine. ApoE null mice fed a Western, pro-atherogenic diet were treated with D-carnosine octylester for 12 weeks. KEY RESULTS In vitro, D-carnosine attenuated the effect of HNE, but not of H(2) O(2) , on VSMCs. In vivo, D-carnosine octylester-treated mice showed reduced lesion area and a more stable plaque phenotype compared with untreated animals, with reduced foam cell accumulation, inflammation and apoptosis and increased clearance of apoptotic bodies and collagen deposition, resulting in decreased necrotic core formation. Likewise, renal lesions were attenuated in D-carnosine octylester-treated versus untreated mice, with lower inflammation, apoptosis and fibrosis. This was associated with increased urinary levels of HNE-carnosine adducts and reduced protein carbonylation, circulating and tissue ALEs, expression of receptors for these products, and systemic and tissue oxidative stress. CONCLUSIONS AND IMPLICATIONS These data indicate RCS quenching with a D-carnosine ester was highly effective in attenuating experimental atherosclerosis and renal disease by reducing carbonyl stress and inflammation and that this may represent a promising therapeutic strategy in humans.
KW - CARNOSINE
KW - DIABETIC NEPHROPATHY
KW - CARNOSINE
KW - DIABETIC NEPHROPATHY
UR - http://hdl.handle.net/10807/15992
UR - http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2012.01834.x/abstract
U2 - 10.1111/j.1476-5381.2012.01834.x
DO - 10.1111/j.1476-5381.2012.01834.x
M3 - Article
SN - 0007-1188
VL - 166
SP - 1344
EP - 1356
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
ER -