Jonas W Brinck1, Aurélien Thomas2, Estelle Lauer2, François R Jornayvaz2, Marie-Claude Brulhart-Meynet2, Jean-Christophe Prost2, Zoltan Pataky2, Patrik Löfgren2, Johan Hoffstedt2, Mats Eriksson2, Camilla Pramfalk2, Sandrine Morel2, Brenda R Kwak2, Miranda van Eck2, Richard W James2, Miguel A Frias2. 1. From the Department of Internal Medicine, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Medical Faculty, Geneva University, Geneva, Switzerland (J.W.B., F.R.J., M.-C.B.-M., R.W.J., M.A.F.); University Centre of Legal Medicine, Unit of Toxicology, Lausanne-Geneva, Switzerland (A.T., E.L., J.-C.P.); Faculty of Biology and Medicine, Lausanne University Hospital, Lausanne University, Lausanne, Switzerland (A.T.); Department of Community Medicine, Service of Therapeutic Education for Chronic Diseases, WHO Collaborating Centre, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland (Z.P.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (J.W.B., P.L., J.H., M.E.); Molecular Nutrition Unit, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden (C.P.); Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden (C.P.); Department of Pathology and Immunology, Medical Faculty, Geneva University, Geneva, Switzerland (S.M., B.R.K.); and Leiden Academic Centre for Drug Research, Division of Biopharmaceutics, Cluster of BioTherapeutics, Leiden University, Leiden, The Netherlands (M.v.E.). jonas.brinck@ki.se. 2. From the Department of Internal Medicine, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Medical Faculty, Geneva University, Geneva, Switzerland (J.W.B., F.R.J., M.-C.B.-M., R.W.J., M.A.F.); University Centre of Legal Medicine, Unit of Toxicology, Lausanne-Geneva, Switzerland (A.T., E.L., J.-C.P.); Faculty of Biology and Medicine, Lausanne University Hospital, Lausanne University, Lausanne, Switzerland (A.T.); Department of Community Medicine, Service of Therapeutic Education for Chronic Diseases, WHO Collaborating Centre, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland (Z.P.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (J.W.B., P.L., J.H., M.E.); Molecular Nutrition Unit, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden (C.P.); Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden (C.P.); Department of Pathology and Immunology, Medical Faculty, Geneva University, Geneva, Switzerland (S.M., B.R.K.); and Leiden Academic Centre for Drug Research, Division of Biopharmaceutics, Cluster of BioTherapeutics, Leiden University, Leiden, The Netherlands (M.v.E.).
Abstract
OBJECTIVE: The dyslipidemia of type 2 diabetes mellitus has multiple etiologies and impairs lipoprotein functionality, thereby increasing risk for cardiovascular disease. High-density lipoproteins (HDLs) have several beneficial effects, notably protecting the heart from myocardial ischemia. We hypothesized that glycation of HDL could compromise this cardioprotective effect. APPROACH AND RESULTS: We used in vitro (cardiomyocytes) and ex vivo (whole heart) models subjected to oxidative stress together with HDL isolated from diabetic patients and nondiabetic HDL glycated in vitro (methylglyoxal). Diabetic and in vitro glycated HDL were less effective (P<0.05) than control HDL in protecting from oxidative stress. Protection was significantly, inversely correlated with the degree of in vitro glycation (P<0.001) and the levels of hemoglobin A1c in diabetic patients (P<0.007). The ability to activate protective, intracellular survival pathways involving Akt, Stat3, and Erk1/2 was significantly reduced (P<0.05) using glycated HDL. Glycation reduced the sphingosine-1-phosphate (S1P) content of HDL, whereas the S1P concentrations of diabetic HDL were inversely correlated with hemoglobin A1c (P<0.005). The S1P contents of in vitro glycated and diabetic HDL were significantly, positively correlated (both <0.01) with cardiomyocyte survival during oxidative stress. Adding S1P to diabetic HDL increased its S1P content and restored its cardioprotective function. CONCLUSIONS: Our data demonstrate that glycation can reduce the S1P content of HDL, leading to increased cardiomyocyte cell death because of less effective activation of intracellular survival pathways. It has important implications for the functionality of HDL in diabetes mellitus because HDL-S1P has several beneficial effects on the vasculature.
OBJECTIVE: The dyslipidemia of type 2 diabetes mellitus has multiple etiologies and impairs lipoprotein functionality, thereby increasing risk for cardiovascular disease. High-density lipoproteins (HDLs) have several beneficial effects, notably protecting the heart from myocardial ischemia. We hypothesized that glycation of HDL could compromise this cardioprotective effect. APPROACH AND RESULTS: We used in vitro (cardiomyocytes) and ex vivo (whole heart) models subjected to oxidative stress together with HDL isolated from diabeticpatients and nondiabetic HDL glycated in vitro (methylglyoxal). Diabetic and in vitro glycated HDL were less effective (P<0.05) than control HDL in protecting from oxidative stress. Protection was significantly, inversely correlated with the degree of in vitro glycation (P<0.001) and the levels of hemoglobin A1c in diabeticpatients (P<0.007). The ability to activate protective, intracellular survival pathways involving Akt, Stat3, and Erk1/2 was significantly reduced (P<0.05) using glycated HDL. Glycation reduced the sphingosine-1-phosphate (S1P) content of HDL, whereas the S1P concentrations of diabetic HDL were inversely correlated with hemoglobin A1c (P<0.005). The S1P contents of in vitro glycated and diabetic HDL were significantly, positively correlated (both <0.01) with cardiomyocyte survival during oxidative stress. Adding S1P to diabetic HDL increased its S1P content and restored its cardioprotective function. CONCLUSIONS: Our data demonstrate that glycation can reduce the S1P content of HDL, leading to increased cardiomyocyte cell death because of less effective activation of intracellular survival pathways. It has important implications for the functionality of HDL in diabetes mellitus because HDL-S1P has several beneficial effects on the vasculature.
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Marie-Claude Brulhart-Meynet; Aurélien Thomas; Jonathan Sidibé; Florian Visentin; Rodolphe Dusaulcy; Valérie Schwitzgebel; Zoltan Pataky; Jacques Philippe; Nicolas Vuilleumier; Richard W James; Yvan Gosmain; Miguel A Frias Journal: Physiol Rep Date: 2021-03