Disease-associated changes in the expression of ion channels, ion receptors, ion exchangers and Ca(2+)-handling proteins in heart hypertrophy.
The molecular pathology of cardiac hypertrophy is multifactorial with transcript regulation of ion channels, ion exchangers and Ca(2+)-handling proteins being speculative. We therefore investigated disease-associated changes in gene expression of various ion channels and their receptors as well as ion exchangers, cytoskeletal proteins and Ca(2+)-handling proteins in normotensive and spontaneously hypertensive (SHR) rats. We also compared experimental findings with results from hypertrophic human hearts, previously published (Borlak, J., and Thum, T., 2003. Hallmarks of ion channel gene expression in end-stage heart failure. FASEB J. 17, 1592-1608). We observed significant (P < 0.05) induction in transcript level of ATP-driven ion exchangers (Atp1A1, NCX-1, SERCA2a), ion channels (L-type Ca(2+)-channel, K(ir)3.4, Na(v)1.5) and RyR-2 in hypertrophic hearts, while gene expression was repressed in diseased human hearts. Further, the genes coding for calreticulin and calmodulin, PMCA 1 and 4 as well as alpha-skeletal actin were significantly (P < 0.05) changed in hypertrophic human heart, but were unchanged in hypertrophic left ventricles of the rat heart. Notably, transcript level of alpha- and beta-MHC, calsequestrin, K(ir)6.1 (in the right ventricle only), phospholamban as well as troponin T were repressed in both diseased human and rat hearts. Our study enabled an identification of disease-associated candidate genes. Their regulation is likely to be the result of an imbalance between pressure load/stretch force and vascular tonus and the observed changes may provide a rational for the rhythm disturbances observed in patients with cardiac hypertrophy.
Zwadlo
Carolin
C
Fraunhofer Institute of Toxicology and Experimental Medicine, Center for Drug Research and Medical Biotechnology, Hannover, Germany.
Borlak
Jürgen
J
D000818:Animals; D001835:Body Weight / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D017931:DNA Primers; D018076:DNA, Complementary / Q000096:biosynthesis; D015870:Gene Expression / Q000502:physiology; D005819:Genetic Markers; D007473:Ion Channels / Q000096:biosynthesis* / Q000235:genetics; D007477:Ions / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000502:physiology; D018384:Oxidative Stress / Q000235:genetics; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D005819:Genetic Markers; D007473:Ion Channels; D007477:Ions; D012313:RNA