Hearts of surviving MLP-KO mice show transient changes of intracellular calcium handling.

Abstract

The muscle Lim protein knock-out (MLP-KO) mouse model is extensively used for studying the pathophysiology of dilated cardiomyopathy. However, explanation is lacking for the observed long survival of the diseased mice which develop until adulthood despite the gene defect, which theoretically predestines them to early death due to heart failure. We hypothesized that adaptive changes of cardiac intracellular calcium (Ca(i)(2+)) handling might explain the phenomenon. In order to study the progression of changes in cardiac function and Ca(i)(2+) cycling, myocardial Ca(i)(2+)-transients recorded by Indo-1 surface fluorometry were assessed with concomitant measurement of hemodynamic performance in isolated Langendorff-perfused hearts of 3- and 9-month old MLP-KO animals. Hearts were challenged with beta-agonist isoproterenol and the sarcoplasmic reticular Ca(2+)-ATPase (SERCA2a) inhibitor cyclopiazonic acid (CPA). Cardiac mRNA content and levels of key Ca(2+) handling proteins were also measured. A decline in lusitropic function was observed in 3-month old, but not in 9-month old MLP-KO mice under unchallenged conditions. beta-adrenergic responses to isoproterenol were similar in all the studied groups. The CPA induced an increase in end-diastolic Ca(i)(2+)-level and a decrease in Ca(2+)-sequestration capacity in 3-month old MLP-KO mice compared to age-matched controls. This unfavorable condition was absent at 9 months of age. SERCA2a expression was lower in 3-month old MLP-KO than in the corresponding controls and in 9-month old MLP-KO hearts. Our results show time-related recovery of hemodynamic function and an age-dependent compensatory upregulation of Ca(i)(2+) handling in hearts of MLP-KO mice, which most likely involve the normalization of the expression of SERCA2a in the affected hearts.

• Authors: Péter Kemecsei, Zsuzsanna Miklós, Tamás Bíró, Rita Marincsák, Balázs I Tóth, Edina Komlódi-Pásztor, Eniko Barnucz, Eva Mirk, Ger J Van der Vusse, László Ligeti, Tamás Ivanics
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 342 Issue 1-2 Pg. 251-60 (Sep 2010) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 20490897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium-Binding Proteins
• Homeodomain Proteins
• Indoles
• LIM Domain Proteins
• Muscle Proteins
• RNA, Messenger
• Ryanodine Receptor Calcium Release Channel
• Tlx2 protein, mouse
• cysteine and glycine-rich protein 3
• phospholamban
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Isoproterenol
• indo-1
• Calcium
• cyclopiazonic acid

Topics

• Age Factors
• Animals
• Blotting, Western
• Body Mass Index
• Calcium (metabolism)
• Calcium-Binding Proteins (genetics, metabolism)
• Heart (physiopathology)
• Heart Failure (metabolism, mortality, pathology)
• Hemodynamics
• Homeodomain Proteins (genetics, metabolism)
• Indoles (pharmacology)
• Isoproterenol (pharmacology)
• LIM Domain Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle Proteins (physiology)
• Myocardium (metabolism, pathology)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (antagonists & inhibitors, metabolism)
• Survival Rate