title: Hypoxia exacerbates Ca(2+)-handling disturbances induced by very low density lipoproteins (VLDL) in neonatal rat cardiomyocytes.
abstract: It is known that myocardium suffers serious alterations under ischemic conditions such as lipid overloading and electrophysiological alterations. However, it is unknown whether intracellular lipid accumulation and calcium dysfunction share common pathophysiological mechanisms under ischemia. The aims of this study were 1) to analyze the effect of normal and high doses of very low density lipoproteins (VLDL) on lipid content and calcium handling; 2) to investigate whether hypoxia modulates the effect of high VLDL doses; and 3) to identify potentially underlying mechanisms in cardiomyocytes. For this purpose, neonatal rat ventricular myocytes cultures were prepared from hearts of 3-4-day-old rats. High doses of VLDL that induced cholesteryl ester (CE) and triglyceride (TG) accumulation strongly reduced sarco(endo)plasmic reticulum Ca ATPase-2 (SERCA-2) expression, calcium transient amplitude and sarcoplasmic reticulum (SR) calcium loading. Interestingly, hypoxia, by upregulating VLDL-receptor expression (4.5-fold at 16h) increased CE (1.5-fold) and TG (3-fold) cardiomyocyte content and exacerbated the negative effect of VLDL on SERCA-2 expression. Functionally, the hypoxic exacerbation of VLDL-mediated SERCA-2 downregulation was translated into a stronger decrease in calcium transient amplitude and SR calcium loading in myocytes exposed simultaneously to hypoxia and high VLDL. In conclusion, high VLDL doses alter calcium handling in cardiomyocytes and SERCA-2 play a pivotal role in the hypoxic exacerbation of VLDL-mediated effects on cardiac calcium handling. Potentiation of VLDL's effects under hypoxia is explained, at least in part, by hypoxic upregulation of the expression of VLDL-receptor.
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Castellano
authors.forename: Jordi
authors.initials: J
authors.lastname: Farré
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Fernandes
authors.forename: Antoni
authors.initials: A
authors.lastname: Bayes-Genis
authors.forename: Juan
authors.initials: J
authors.lastname: Cinca
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
authors.forename: Leif
authors.initials: L
authors.lastname: Hove-Madsen
authors.forename: Vicenta
authors.initials: V
authors.lastname: Llorente-Cortés
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar
chemical_list: D008079:Lipoproteins, VLDL; D002118:Calcium