Molecular and functional remodeling of Ito by angiotensin II in the mouse left ventricle

Tozakidou, Magdalini; Goltz, Diane; Hagenström, Till; Budack, Mareike K.; Vitzthum, Helga; Szlachta, Kamila; Bähring, Robert; Ehmke, Heimo

doi:10.1016/j.yjmcc.2009.08.027

Cited by 14 publications

(8 citation statements)

References 38 publications

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“…Furthermore, the rise in mRNA levels of potassium channel β-subunit KChIP2 produced by myocardial infarction was cancelled out by GF administration. Recent studies documented higher mRNA levels of KChIP2 in cardiac hypertrophy [50] although a full appreciation of this result is impossible, since to date the role of KChip(s) subunit(s) has not been clearly elucidated. In conclusion, the lower mRNA levels of Kv1.4 and KChIP2 subunits produced by GF injection might be associated with the reduced reactive cellular hypertrophy following cardiac repair.…”

Section: Discussionmentioning

confidence: 99%

Growth Factor-Induced Mobilization of Cardiac Progenitor Cells Reduces the Risk of Arrhythmias, in a Rat Model of Chronic Myocardial Infarction

et al. 2011

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Heart repair by stem cell treatment may involve life-threatening arrhythmias. Cardiac progenitor cells (CPCs) appear best suited for reconstituting lost myocardium without posing arrhythmic risks, being commissioned towards cardiac phenotype. In this study we tested the hypothesis that mobilization of CPCs through locally delivered Hepatocyte Growth Factor and Insulin-Like Growth Factor-1 to heal chronic myocardial infarction (MI), lowers the proneness to arrhythmias. We used 133 adult male Wistar rats either with one-month old MI and treated with growth factors (GFs, n = 60) or vehicle (V, n = 55), or sham operated (n = 18). In selected groups of animals, prior to and two weeks after GF/V delivery, we evaluated stress-induced ventricular arrhythmias by telemetry-ECG, cardiac mechanics by echocardiography, and ventricular excitability, conduction velocity and refractoriness by epicardial multiple-lead recording. Invasive hemodynamic measurements were performed before sacrifice and eventually the hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. When compared with untreated MI, GFs decreased stress-induced arrhythmias and concurrently prolonged the effective refractory period (ERP) without affecting neither the duration of ventricular repolarization, as suggested by measurements of QTc interval and mRNA levels for K-channel α-subunits Kv4.2 and Kv4.3, nor the dispersion of refractoriness. Further, markers of cardiomyocyte reactive hypertrophy, including mRNA levels for K-channel α-subunit Kv1.4 and β-subunit KChIP2, interstitial fibrosis and negative structural remodeling were significantly reduced in peri-infarcted/remote ventricular myocardium. Finally, analyses of BrdU incorporation and distribution of connexin43 and N-cadherin indicated that cytokines generated new vessels and electromechanically-connected myocytes and abolished the correlation of infarct size with deterioration of mechanical function. In conclusion, local injection of GFs ameliorates electromechanical competence in chronic MI. Reduced arrhythmogenesis is attributable to prolongation of ERP resulting from improved intercellular coupling via increased expression of connexin43, and attenuation of unfavorable remodeling.

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Section: Discussionmentioning

confidence: 99%

Growth Factor-Induced Mobilization of Cardiac Progenitor Cells Reduces the Risk of Arrhythmias, in a Rat Model of Chronic Myocardial Infarction

et al. 2011

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“…Reductions in K v 4.2 and K v 4.3 expression have been demonstrated in heart failure and hypertrophy, concordant with the cardiac K v 4.2/K v 4.3 downregulation noted in epilepsy . Indeed, decreased K + channel expression appears conserved across animals with failing hearts secondary to (a) dilated cardiomyopathy, (b) angiotensin II‐mediated hypertrophy, (c) primary hypertension, and (d) ventricular tachypacing, increasing the likelihood that an epilepsy‐associated cardiac K + channelopathy is also mediated by structural dysfunction. Moreover, these animal models reflect the cardioautonomic changes seen in epilepsy, including sympathetic overactivity, ventricular remodeling, and systolic and diastolic failure …”

Section: Pathophysiology Of Altered Cardiac Ion Channel Expression Inmentioning

confidence: 60%

“…Primary cardiomyopathic changes alter the transcriptional regulation of voltage‐gated potassium channels involved in both early (K v 1.4/K v 4.2/K v 4.3) and delayed (K v 1.5/K v 7.1) action potential repolarization . Reductions in K v 4.2 and K v 4.3 expression have been demonstrated in heart failure and hypertrophy, concordant with the cardiac K v 4.2/K v 4.3 downregulation noted in epilepsy . Indeed, decreased K + channel expression appears conserved across animals with failing hearts secondary to (a) dilated cardiomyopathy, (b) angiotensin II‐mediated hypertrophy, (c) primary hypertension, and (d) ventricular tachypacing, increasing the likelihood that an epilepsy‐associated cardiac K + channelopathy is also mediated by structural dysfunction.…”

Section: Pathophysiology Of Altered Cardiac Ion Channel Expression Inmentioning

confidence: 78%

Acquired cardiac channelopathies in epilepsy: Evidence, mechanisms, and clinical significance

O’Brien

Todaro

et al. 2019

Epilepsia

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There is growing evidence that cardiac dysfunction in patients with chronic epilepsy could play a pathogenic role in sudden unexpected death in epilepsy (SUDEP). Recent animal studies have revealed that epilepsy secondarily alters the expression of cardiac ion channels alongside abnormal cardiac electrophysiology and remodeling. These molecular findings represent novel evidence for an acquired cardiac channelopathy in epilepsy, distinct from inherited ion channels mutations associated with cardiocerebral phenotypes. Specifically, seizure activity has been shown to alter the messenger RNA (mRNA) and protein expression of voltage‐gated sodium channels (Nav1.1, Nav1.5), voltage‐gated potassium channels (Kv4.2, Kv4.3), sodium‐calcium exchangers (NCX1), and nonspecific cation‐conducting channels (HCN2, HCN4). The pathophysiology may involve autonomic dysfunction and structural cardiac disease, as both are independently associated with epilepsy and ion channel dysregulation. Indeed, in vivo and in vitro studies of cardiac pathology reveal a complex network of signaling pathways and transcription factors regulating ion channel expression in the setting of sympathetic overactivity, cardiac failure, and hypertrophy. Other mechanisms such as circulating inflammatory mediators or exogenous effects of antiepileptic medications lack evidence. Moreover, an acquired cardiac channelopathy may underlie the electrophysiologic cardiac abnormalities seen in chronic epilepsy, potentially contributing to the increased risk of malignant arrhythmias and sudden death. Therefore, further investigation is necessary to establish whether cardiac ion channel dysregulation similarly occurs in patients with epilepsy, and to characterize any pathogenic relationship with SUDEP.

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“…In order to isolate I to from the compound outward current in murine cardiomyocytes and to measure its amplitude and decay kinetics a prepulse-inactivation-subtraction method has been frequently used ([ 9 , 23 , 27 , 28 ]; see also Fig 1A and S1 Fig of the present study). This method relies on the complete inactivation of I to -related potassium channels by a depolarizing prepulse which must not gate any other potassium channels.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, both prepulse length and prepulse voltage are critical parameters. Typically, prepulse lengths between 75 ms [ 9 ] and 120 ms [ 27 ] and a prepulse voltage of -40 mV have been used. In the present study the prepulse-inactivation-subtraction method was applied to male myocytes using a prepulse length of 160 ms and a prepulse voltage of -40 mV ( Fig 1A and S1 Fig ).…”

Section: Discussionmentioning

confidence: 99%

KChIP2 genotype dependence of transient outward current (Ito) properties in cardiomyocytes isolated from male and female mice

2017

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The transient outward current (Ito) in cardiomyocytes is largely mediated by Kv4 channels associated with Kv Channel Interacting Protein 2 (KChIP2). A knockout model has documented the critical role of KChIP2 in Ito expression. The present study was conducted to characterize in both sexes the dependence of Ito properties, including current magnitude, inactivation kinetics, recovery from inactivation and voltage dependence of inactivation, on the number of functional KChIP2 alleles. For this purpose we performed whole-cell patch-clamp experiments on isolated left ventricular cardiomyocytes from male and female mice which had different KChIP2 genotypes; i.e., wild-type (KChIP2+/+), heterozygous knockout (KChIP2+/-) or complete knockout of KChIP2 (KChIP2-/-). We found in both sexes a KChIP2 gene dosage effect (i.e., a proportionality between number of alleles and phenotype) on Ito magnitude, however, concerning other Ito properties, KChIP2+/- resembled KChIP2+/+. Only in the total absence of KChIP2 (KChIP2-/-) we observed a slowing of Ito kinetics, a slowing of recovery from inactivation and a negative shift of a portion of the voltage dependence of inactivation. In a minor fraction of KChIP2-/- myocytes Ito was completely lost. The distinct KChIP2 genotype dependences of Ito magnitude and inactivation kinetics, respectively, seen in cardiomyocytes were reproduced with two-electrode voltage-clamp experiments on Xenopus oocytes expressing Kv4.2 and different amounts of KChIP2. Our results corroborate the critical role of KChIP2 in controlling Ito properties. They demonstrate that the Kv4.2/KChIP2 interaction in cardiomyocytes is highly dynamic, with a clear KChIP2 gene dosage effect on Kv4 channel surface expression but not on inactivation gating.

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Molecular and functional remodeling of Ito by angiotensin II in the mouse left ventricle

Cited by 14 publications

References 38 publications

Growth Factor-Induced Mobilization of Cardiac Progenitor Cells Reduces the Risk of Arrhythmias, in a Rat Model of Chronic Myocardial Infarction

Growth Factor-Induced Mobilization of Cardiac Progenitor Cells Reduces the Risk of Arrhythmias, in a Rat Model of Chronic Myocardial Infarction

Acquired cardiac channelopathies in epilepsy: Evidence, mechanisms, and clinical significance

KChIP2 genotype dependence of transient outward current (Ito) properties in cardiomyocytes isolated from male and female mice

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