AIMS: Here we investigated the mechanisms by which cardiovascular CB1 cannabinoid receptors may modulate the cardiac dysfunction, oxidative stress, and interrelated cell death pathways associated with acute/chronic cardiomyopathy induced by the widely used anti-tumour compound doxorubicin (DOX). METHODS AND RESULTS: Both load-dependent and -independent indices of left-ventricular function were measured by the Millar pressure-volume conductance system. Mitogen-activated protein kinase (MAPK) activation, cell-death markers, and oxidative/nitrosative stress were measured by molecular biology/biochemical methods and flow cytometry. DOX induced left-ventricular dysfunction, oxidative/nitrosative stress coupled with impaired antioxidant defense, activation of MAPK (p38 and JNK), and cell death and/or fibrosis in hearts of wide-type mice (CB1(+/+)), and these effects were markedly attenuated in CB1 knockouts (CB1(-/-)). In human primary cardiomyocytes expressing CB1 receptors (demonstrated by RT-PCR, western immunoblot, and flow cytometry) DOX, likewise the CB1 receptor agonist HU210 and the endocannabinoid anandamide (AEA), induced MAPK activation and cell death. The DOX-induced MAPK activation and cell death were significantly enhanced when DOX was co-administered with CB1 agonists AEA or HU210. Remarkably, cell death and MAPK activation induced by AEA, HU210, and DOX +/- AEA/HU210 were largely attenuated by either CB1 antagonists (rimonabant and AM281) or by inhibitors of p38 and JNK MAPKs. Furthermore, AEA or HU210 in primary human cardiomyocytes triggered increased reactive oxygen species generation. CONCLUSION: CB1 activation in cardiomyocytes may amplify the reactive oxygen/nitrogen species-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, which may contribute to the pathophysiology of various cardiovascular diseases.
AIMS: Here we investigated the mechanisms by which cardiovascular CB1 cannabinoid receptors may modulate the cardiac dysfunction, oxidative stress, and interrelated cell death pathways associated with acute/chronic cardiomyopathy induced by the widely used anti-tumour compound doxorubicin (DOX). METHODS AND RESULTS: Both load-dependent and -independent indices of left-ventricular function were measured by the Millar pressure-volume conductance system. Mitogen-activated protein kinase (MAPK) activation, cell-death markers, and oxidative/nitrosative stress were measured by molecular biology/biochemical methods and flow cytometry. DOX induced left-ventricular dysfunction, oxidative/nitrosative stress coupled with impaired antioxidant defense, activation of MAPK (p38 and JNK), and cell death and/or fibrosis in hearts of wide-type mice (CB1(+/+)), and these effects were markedly attenuated in CB1 knockouts (CB1(-/-)). In human primary cardiomyocytes expressing CB1 receptors (demonstrated by RT-PCR, western immunoblot, and flow cytometry) DOX, likewise the CB1 receptor agonist HU210 and the endocannabinoidanandamide (AEA), induced MAPK activation and cell death. The DOX-induced MAPK activation and cell death were significantly enhanced when DOX was co-administered with CB1 agonists AEA or HU210. Remarkably, cell death and MAPK activation induced by AEA, HU210, and DOX +/- AEA/HU210 were largely attenuated by either CB1 antagonists (rimonabant and AM281) or by inhibitors of p38 and JNK MAPKs. Furthermore, AEA or HU210 in primary human cardiomyocytes triggered increased reactive oxygen species generation. CONCLUSION:CB1 activation in cardiomyocytes may amplify the reactive oxygen/nitrogen species-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, which may contribute to the pathophysiology of various cardiovascular diseases.
Authors: Tatsuo Katori; Sonia Donzelli; Carlo G Tocchetti; Katrina M Miranda; Gianfrancesco Cormaci; Douglas D Thomas; Elizabeth A Ketner; Myung Jae Lee; Daniele Mancardi; David A Wink; David A Kass; Nazareno Paolocci Journal: Free Radic Biol Med Date: 2006-09-05 Impact factor: 7.376
Authors: David A Gorelick; Stephen J Heishman; Kenzie L Preston; Richard A Nelson; Eric T Moolchan; Marilyn A Huestis Journal: Am Heart J Date: 2006-03 Impact factor: 4.749
Authors: Francesco Timolati; Daniel Ott; Laura Pentassuglia; Marie-Noëlle Giraud; Jean-Claude Perriard; Thomas M Suter; Christian Zuppinger Journal: J Mol Cell Cardiol Date: 2006-09-26 Impact factor: 5.000
Authors: Sándor Bátkai; Pál Pacher; Douglas Osei-Hyiaman; Svetlana Radaeva; Jie Liu; Judith Harvey-White; László Offertáler; Ken Mackie; M Audrey Rudd; Richard D Bukoski; George Kunos Journal: Circulation Date: 2004-09-27 Impact factor: 29.690
Authors: Reynolds M Delgado; Mohamad A Nawar; Aly M Zewail; Biswajit Kar; William K Vaughn; Kenneth K Wu; Nena Aleksic; Natarajan Sivasubramanian; Kathleen McKay; Douglas L Mann; James T Willerson Journal: Circulation Date: 2004-03-15 Impact factor: 29.690
Authors: Blerina Kola; Gábor Wittman; Ibolya Bodnár; Faisal Amin; Chung Thong Lim; Márk Oláh; Mirjam Christ-Crain; Francesca Lolli; Hinke van Thuijl; Chrysanthia A Leontiou; Tamás Füzesi; Paolo Dalino; Andrea M Isidori; Judith Harvey-White; George Kunos; György M Nagy; Ashley B Grossman; Csaba Fekete; Márta Korbonits Journal: FASEB J Date: 2013-08-27 Impact factor: 5.191
Authors: Partha Mukhopadhyay; Mohanraj Rajesh; Béla Horváth; Sándor Bátkai; Ogyi Park; Galin Tanchian; Rachel Y Gao; Vivek Patel; David A Wink; Lucas Liaudet; György Haskó; Raphael Mechoulam; Pál Pacher Journal: Free Radic Biol Med Date: 2011-03-11 Impact factor: 7.376