Early cardiac dysfunction is rescued by upregulation of SERCA2a pump activity in a rat model of metabolic syndrome

Z. Miklós, P. Kemecsei, T. Bíró, R. Marincsák, B. I. Tóth, J. Op den Buijs, É Benis, A. Drozgyik, T. Ivanics

Research output: Contribution to journalArticle

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Abstract

Aim: 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. Method: 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) Ca2+-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 Ca2+ transporters. Protein levels of key Ca2+ 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 Ca2+ sequestration capacity (-dCai 2+/dt and decay time of Cai 2+ transients) was observed. Model estimation showed decreased affinity for Ca2+ (higher Km) and elevated Vmax 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)381-393
Number of pages13
JournalActa Physiologica
Volume205
Issue number3
DOIs
Publication statusPublished - Jul 2012

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Fructose
Up-Regulation
Sarcoplasmic Reticulum
Echocardiography
Theoretical Models
Hemodynamics
Precipitating Factors
Fluorometry
Proteins
Calcium-Transporting ATPases
Cardiomegaly
Dyslipidemias
Insulin Resistance
Heart Diseases
Heart Failure
Phosphorylation
Hypertension
Calcium
phospholamban
cyclopiazonic acid

Keywords

  • Cai 2+ handling
  • Echocardiography
  • Isolated hearts
  • Metabolic syndrome
  • SERCA2a

ASJC Scopus subject areas

  • Physiology

Cite this

Early cardiac dysfunction is rescued by upregulation of SERCA2a pump activity in a rat model of metabolic syndrome. / Miklós, Z.; Kemecsei, P.; Bíró, T.; Marincsák, R.; Tóth, B. I.; Op den Buijs, J.; Benis, É; Drozgyik, A.; Ivanics, T.

In: Acta Physiologica, Vol. 205, No. 3, 07.2012, p. 381-393.

Research output: Contribution to journalArticle

Miklós, Z, Kemecsei, P, Bíró, T, Marincsák, R, Tóth, BI, Op den Buijs, J, Benis, É, Drozgyik, A & Ivanics, T 2012, 'Early cardiac dysfunction is rescued by upregulation of SERCA2a pump activity in a rat model of metabolic syndrome', Acta Physiologica, vol. 205, no. 3, pp. 381-393. https://doi.org/10.1111/j.1748-1716.2012.02420.x
Miklós, Z. ; Kemecsei, P. ; Bíró, T. ; Marincsák, R. ; Tóth, B. I. ; Op den Buijs, J. ; Benis, É ; Drozgyik, A. ; Ivanics, T. / Early cardiac dysfunction is rescued by upregulation of SERCA2a pump activity in a rat model of metabolic syndrome. In: Acta Physiologica. 2012 ; Vol. 205, No. 3. pp. 381-393.
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abstract = "Aim: 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. Method: 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) Ca2+-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 Ca2+ transporters. Protein levels of key Ca2+ 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 Ca2+ sequestration capacity (-dCai 2+/dt and decay time of Cai 2+ transients) was observed. Model estimation showed decreased affinity for Ca2+ (higher Km) and elevated Vmax 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. Conclusion: 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.",
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AU - Bíró, T.

AU - Marincsák, R.

AU - Tóth, B. I.

AU - Op den Buijs, J.

AU - Benis, É

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