OBJECTIVE: High density lipoproteins (HDL) protect against ischemia reperfusion injury (IRI). However the precise mechanisms are not clearly understood. The novel intrinsic prosurvival signaling pathway named survivor activating factor enhancement (SAFE) path involves the activation of tumor necrosis factor (TNF) alpha and signal transducer and activator of transcription 3 (STAT3). SAFE plays a crucial role in cardioprotection against IRI. We propose that HDL protect against IRI via activation of the SAFE pathway and modulation of the mitochondrial permeability transition pore (mPTP) opening. METHODS AND RESULTS: Isolated mouse hearts were subjected to global ischemia (35 min) followed by reperfusion (45 min). HDL were given during the first 7 min of reperfusion. In control hearts, the post-reperfusion infarct size was 41.3 ± 2.3%. Addition of HDL during reperfusion reduced the infarct size in a dose-dependent manner (HDL 200 μg protein/ml: 25.5 ± 1.6%, p < 0.001 vs. control). This protective effect was absent in TNF deficient mice (TNF-KO) or cardiomyocyte-STAT3 deficient mice (STAT3-KO). Similarly, HDL, given as a preconditioning stimulus, improved cell survival and inhibited mPTP opening in isolated cardiomyocytes subjected to simulated ischemia. These protective responses were inhibited in cardiomyocytes from TNF-KO and STAT3-KO mice. CONCLUSION: Our data demonstrate that HDL protect against IRI by inhibition of mPTP opening, an effect mediated via activation of the SAFE pathway.
OBJECTIVE: High density lipoproteins (HDL) protect against ischemia reperfusion injury (IRI). However the precise mechanisms are not clearly understood. The novel intrinsic prosurvival signaling pathway named survivor activating factor enhancement (SAFE) path involves the activation of tumor necrosis factor (TNF) alpha and signal transducer and activator of transcription 3 (STAT3). SAFE plays a crucial role in cardioprotection against IRI. We propose that HDL protect against IRI via activation of the SAFE pathway and modulation of the mitochondrial permeability transition pore (mPTP) opening. METHODS AND RESULTS: Isolated mouse hearts were subjected to global ischemia (35 min) followed by reperfusion (45 min). HDL were given during the first 7 min of reperfusion. In control hearts, the post-reperfusion infarct size was 41.3 ± 2.3%. Addition of HDL during reperfusion reduced the infarct size in a dose-dependent manner (HDL 200 μg protein/ml: 25.5 ± 1.6%, p < 0.001 vs. control). This protective effect was absent in TNF deficientmice (TNF-KO) or cardiomyocyte-STAT3 deficientmice (STAT3-KO). Similarly, HDL, given as a preconditioning stimulus, improved cell survival and inhibited mPTP opening in isolated cardiomyocytes subjected to simulated ischemia. These protective responses were inhibited in cardiomyocytes from TNF-KO and STAT3-KO mice. CONCLUSION: Our data demonstrate that HDL protect against IRI by inhibition of mPTP opening, an effect mediated via activation of the SAFE pathway.
Authors: Marie-Claude Brulhart-Meynet; Vincent Braunersreuther; Jonas Brinck; Fabrizio Montecucco; Jean-Christophe Prost; Aurelien Thomas; Katia Galan; Graziano Pelli; Sarah Pedretti; Nicolas Vuilleumier; François Mach; Sandrine Lecour; Richard W James; Miguel A Frias Journal: PLoS One Date: 2015-03-17 Impact factor: 3.240
Authors: Derek J Hausenloy; Jose A Barrabes; Hans Erik Bøtker; Sean M Davidson; Fabio Di Lisa; James Downey; Thomas Engstrom; Péter Ferdinandy; Hector A Carbrera-Fuentes; Gerd Heusch; Borja Ibanez; Efstathios K Iliodromitis; Javier Inserte; Robert Jennings; Neena Kalia; Rajesh Kharbanda; Sandrine Lecour; Michael Marber; Tetsuji Miura; Michel Ovize; Miguel A Perez-Pinzon; Hans Michael Piper; Karin Przyklenk; Michael Rahbek Schmidt; Andrew Redington; Marisol Ruiz-Meana; Gemma Vilahur; Jakob Vinten-Johansen; Derek M Yellon; David Garcia-Dorado Journal: Basic Res Cardiol Date: 2016-10-20 Impact factor: 17.165