title: Early cardiac dysfunction is rescued by upregulation of SERCA2a pump activity in a rat model of metabolic syndrome.
abstract: OBJECTIVE
  Various components of metabolic syndrome associate with cardiac intracellular calcium (Cai 2+) mishandling, a precipitating factor in the development of heart failure. We aimed to provide a thorough description of early stage Cai 2+-cycling alterations in the fructose-fed rat, an experimental model of the disorder, where insulin resistance, hypertension and dyslipidaemia act cooperatively on the heart.
  
  
  METHODS
  Rats were fed with fructose-rich chow. After 6 weeks, echocardiography was performed, which was followed by measurements of myocardial Cai 2+ transients recorded by Indo-1 surface fluorometry in isolated perfused hearts. Sarcoplasmic reticulum (SR) Ca(2+) -ATPase (SERCA2a) activity was assessed by administration of its inhibitor cyclopiazonic acid (CPA). Mathematical model analysis of Cai 2+ transients was used to estimate kinetic properties of SR Ca(2+) transporters. Protein levels of key Ca(2+) handling proteins were also measured.
  
  
  RESULTS
  Echocardiography showed signs of cardiac hypertrophy, but in vivo and ex vivo haemodynamic performance of fructose-fed rat hearts were unaltered. However, a decline in Ca(2+) sequestration capacity (-dCai 2+/dt and decay time of Cai 2+ transients) was observed. Model estimation showed decreased affinity for Ca(2+) (higher K(m) ) and elevated V(max) for SERCA2a. Diseased hearts were more vulnerable to CPA application. Fructose feeding caused elevation in SERCA2a and phosphorylated phospholamban (PLB) expression, while total PLB level remained unchanged.
  
  
  CONCLUSIONS
  In early stage, metabolic syndrome primarily disturbs SERCA2a function in the heart, but consequential haemodynamic dysfunction is prevented by upregulation of SERCA2a protein level and phosphorylation pathways regulating PLB. However, this compensated state is very vulnerable to a further decline in SERCA2a function.
authors.affiliation: Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Miklós
authors.forename: P
authors.initials: P
authors.lastname: Kemecsei
authors.forename: T
authors.initials: T
authors.lastname: Bíró
authors.forename: R
authors.initials: R
authors.lastname: Marincsák
authors.forename: B I
authors.initials: BI
authors.lastname: Tóth
authors.forename: J
authors.initials: J
authors.lastname: Op den Buijs
authors.forename: É
authors.initials: É
authors.lastname: Benis
authors.forename: A
authors.initials: A
authors.lastname: Drozgyik
authors.forename: T
authors.initials: T
authors.lastname: Ivanics
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D006321:Heart / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism*; D008962:Models, Theoretical; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban