© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Reexpression of T-type Ca channels after myocardial infarction: does it play a role in cardiac excitation?
Diakonessenhuis Utrecht, Interne Geneeskunde, Bosboomstraat 3, 3582 KE Utrecht, The Netherlands
* Tel.: +31-30-2566-566; fax: +31-30-2566-738
Received 13 March 2000; accepted 13 March 2000
See article by Huang et al. [5] (pages 442–449) in this issue.
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Introduction |
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 Top Introduction Cardiac Ca2+ channelsT-type Ca2+ channel in...Reexpression of fetal T-type...Post-infarction myocardial...References |
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Electrophysiological and myocardial remodeling plays an important role in the development of heart failure and arrhythmogenesis after myocardial infarction. Previous reports [1–4] have shown that the activation of signal transduction pathways after myocardial infarction involved in the initiation of cardiac hypertrophy follows a distinct pattern. Why do fetal and neonatal isogenes become reactivated under pathologic conditions? Recent studies [5–7] have taught us that expression and function of ion channels is very dynamic and can be affected at various levels depending on various physiologic and adverse stimuli. The pattern of cardiac excitation, pathologic stimuli such as ischemia or infarction and rate of impulse propagation have important effects on ion channel expression and properties. The number, biophysical characteristics and distribution of ion channels is affected by mRNA transcription and protein translation rates, post-translational modifications, rate of cellular turn-over of ion channel proteins and phosphorylation level of important amino acid residues on the channel protein. Huang and his associates [5] present data that is of substantial importance in enhancing our understanding of the underlying mechanisms of ionic remodeling after myocardial infarction. Specifically, they present data on the reexpression of T-type Ca channel in post-infarction viable left ventricular myocytes.
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Cardiac Ca2+ channels |
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TopIntroductionCardiac Ca2+ channelsT-type Ca2+ channel in...Reexpression of fetal T-type...Post-infarction myocardial...References |
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In the heart, two types of Ca channels have been identified that are expressed on the sarcolemma of cardiomyocytes: the longlasting type of high voltage activated Ca channel (ICa, L) and the low voltage activated transient Ca channel (ICa, T). The L-type Ca current plays an important role in maintaining the plateau phase of the action potential, and providing influx of Ca ions to initiate cardiac contraction. The T-type Ca current plays a prominent role in nodal cells and embryonic cardiomyocytes and has been associated with cell growth [4–7]. However, ICa, T has little effect on cardiac excitation-contraction coupling. In addition to being involved in growth and development, ICa, T can modulate electrophysiological properties by providing a window current between –60 and –20 mV which will increase an inward current at the end of the plateau and may facilitate the appearance of early after depolarizations. Marked hypertrophy occurs in viable regions of myocardium after myocardial infarction, and severe left ventricular dysfunction ensues later. The prolonged action potential duration in postmyocardial infarction remodeled hypertrophied cardiomyocytes is caused by a decreased density of both slow and fast transient outward potassium currents. The decrease in current density was explained by characteristic alterations in the expression of the different voltage-gated potassium channel subunit genes. The authors of the present study [5] have shown previously that 3–4 weeks after myocardial infarction, isolated remodeled hypertrophied cardiomyocytes exhibit early and late after depolarizations.
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T-type Ca2+ channel in growth and hypertrophy |
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TopIntroductionCardiac Ca2+ channelsT-type Ca2+ channel in...Reexpression of fetal T-type...Post-infarction myocardial...References |
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Cardiac myocytes become terminally differentiated after birth, and in adult life respond to pathologic stimuli by hypertrophy. Marked hypertrophy occurs in viable regions of myocardium after myocardial infarction, compromised LV function and heart failure ensues later [1–4]. During cardiac hypertrophy, cardiomyocytes dramatically change their pattern of gene expression with consequences for both mechanical and electrophysiological properties. These changes include the induction of immediate-early response genes (proto-oncogene c-fos, c-jun), the induction of fetal and neonatal genes, e.g. β-myosin heavy chain (β-MHC), L-type Ca channel and Na-K ATPase and upregulation of constitutively expressed contractile proteins. These alterations result in an increase in the production and assembly of contractile proteins into sarcomeric units and an increase in the efficiency of contraction and decrease in wall stress. Clinical studies have shown that cardiac hypertrophy is not only an adaptational state before cardiac failure, but also an independent risk factor for sudden cardiac death due to lethal ventricular tachyarrhythmias. The presence of interstitial fibrosis, areas of slow conduction and hypertrophied cardiomyocytes in the peri-infarct zone may facilitate arrhythmias based on both reentry and triggered activity. Hypertrophied cardiomyocytes show a prolonged action potential which will increase the likelihood of triggered activity.
There is a growing body of evidence that ICa, T is associated with the development and growth processes [2–4]. The expression of T-type Ca channel protein increases in atrial myocytes from adult rats with growth hormone secreting tumors. Endothelin-1 and angiotensin II, two endogenous peptides which are able to induce cardiac hypertrophy, also enhance ICa, T in cultured neonatal rat ventricular myocytes. Myocardial hypertrophy is characterized by reexpression of fetal and neonatal genes in the adult myocyte. The biological cascade that occurs during pathological events, such as mechanical overload, causes the cardiomyocytes to utilize the fetal genetic program. Work overload is accompanied by an induction of β-MHC causing a shift of the isomyosins. Thus, cardiac hypertrophy after myocardial infarction involves a shift in the expression of several isogenes towards a fetal program of gene expression.
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Reexpression of fetal T-type Ca2+ channel isogenes |
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TopIntroductionCardiac Ca2+ channelsT-type Ca2+ channel in...Reexpression of fetal T-type...Post-infarction myocardial...References |
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The availability of recombinant T-type calcium channels for expression in cell systems and subsequently pharmacologic and biophysical characterization opens a new area of research and provides the necessary tools to unravel the ionic and molecular mechanisms of ion channel functions. The present study published in this issue of the Journal [5] shows that both alpha-1H and alpha-1G of the T-type Ca channel genes and currents are reexpressed in the rat postmyocardial infarction remodeled left ventricle which is consistent with the reemergence of fetal and neonatal isogene patterns under pathologic conditions. Native ICa, T is always superimposed on the ICa, L, making detailed functional characterization of T-type Ca channel difficult. The authors of the present study have elegantly shown that both Ca channel gene and current becomes reexpressed after myocardial infarction. The physiological significance of their findings remains to be determined. Correlation of the transcript levels of T- and L-type Ca channels with electrophysiological data in the subacute phase of myocardial infarction would enhace our knowledge of the arrhythmogenesis at these stages. The consequence of selective inhibition of T-type channels on in vivo ventricular arrhythmias seen in the experimental subacute stage of myocardial infarction would be of interest. Because of the significant consequences of altered gene expression on postmyocardial infarction electrophysiological and mechanical functions of the heart, further investigation of postmyocardial infarction signal transduction pathways is needed. It is important to realize that so far, the role of T-type Ca channel has not been demonstrated in cardiomyocytes from patients with different cardiac diseases including heart failure. The T-type calcium channel blocker, mibefradil, has been used in clinical trials, however, it was soon withdrawn due to serious interactions with several other drugs.
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Post-infarction myocardial remodeling and arrhythmogenesis |
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TopIntroductionCardiac Ca2+ channelsT-type Ca2+ channel in...Reexpression of fetal T-type...Post-infarction myocardial...References |
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Cardiac ion channels play an important role in regulating cardiac excitable and contractile properties. Why is postinfarction heart failure associated with a specific pattern of alterations in ion channel expression and function? Are these changes adaptive or are they merely a function of reactivation of a fetal and neonatal genetic program? Alterations in mRNA expression appears to play a central role caused by transcriptional up or downregulation of gene expression. Electrophysiological and structural remodeling caused by heart failure contributes significantly to an increased risk of sudden cardiac death, especially after myocardial infarction. There is growing evidence supporting the concept that ionic remodeling is associated with structural remodeling such as hypertrophy. The physiological role of the reexpression of T-type Ca channel gene and protein in viable cardiomyocytes in the subacute phase of myocardial infarction still remains to be determined. Helicopter view of the remodeling process after myocardial infarction shows us that T-type Ca channel is one of the many components involved in the alterations leading to contractile dysfunction and arrhythmogenesis. Inherent to all research, the present study [5] leads to new questions and problems and thus goals for further research. Additional studies need to delineate the functional importance of the genetic alterations associated with post-infarction remodeling. Future experimental studies will have to show that interfering with the process of remodeling by blocking a critical step in the regulatory process prevents development of arrhythmogenic substrates. The fast development in cardiac molecular physiology and genetics will enable us to broaden our understanding of the mechanisms of cardiac pathology and provide new tools for intervention in the near future.
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References |
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TopIntroductionCardiac Ca2+ channelsT-type Ca2+ channel in...Reexpression of fetal T-type...Post-infarction myocardial...References |
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- Marban E., Koretsune Y. Cell calcium, oncogenes and hypertrophy. Hypertension (1990) 15:652–658.
[Abstract/Free Full Text] - Xu X., Best P.M. Increase in T-type calcium current in atrial myocytes from adult rats with growth-hormone secreting tumors. Proc Natl Acad Sci USA (1990) 87:4655–4659.
[Abstract/Free Full Text] - Xu X., Best P.M. Postnatal changes in T-type calcium current density in rat atrial myocytes. J Physiol. (1992) 454:657–672.
[Abstract/Free Full Text] - Nuss H.B., Houser S.R. T-type Ca current is expressed in hypertrophied adult feline left ventricular myocytes. Circ Res (1993) 73:777–782.
[Abstract/Free Full Text] - Huang B., Qin D., Deng L., Boutjdir M., El-Sherif N. Reexpression of T-type Ca channel gene and current in post-infarction remodeled rat left ventricle. Current issue of Cardiovasc Res. (2000) 46:442–449.
- Perez-Reyes E., Cribbs L.L., Daud A., Lacerda A.E., Barclay J., Williamson M.P., Fox M., Rees M., Lee J. Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature (1998) 391:896–900.[CrossRef][Medline]
- Cribbs L.L., Lee J., Yang J., Satin J., Zhang Y., Daud A., Barclay J., Williamson M.P., Fox M., Rees M., Perez-Reyes E. Cloning and characterization of
1H from human heart, a member of the T-type Ca channel gene family. Circ Res (1998) 83:103–109.[Abstract/Free Full Text]
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