Gene dose-dependent atrial arrhythmias, heart block, and brady-cardiomyopathy in mice overexpressing A3 adenosine receptors

Fabritz, Larissa; Kirchhof, Paulus; Fortmüller, Lisa; Auchampach, John A.; Baba, Hideo A.; Breithardt, Günter; Neumann, Joachim; Boknı́k, Peter; Schmitz, Wilhelm

doi:10.1016/j.cardiores.2004.02.004

Cited by 45 publications

(35 citation statements)

References 34 publications

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“…In a similar way, in isolated work-performing hearts, isoproterenol increased the phosphorylation of PLB at Ser 16 (and Thr 17 ) in TG and WT mice. However, 5-HT enhanced the phosphorylation of PLB at Ser 16 (and Thr 17 ) only in perfused hearts from TG mice but not from WT mice (Fig. 4A).…”

Section: Resultsmentioning

confidence: 64%

“…The ratios (TG/WT) of the mean expression levels were as follows: SERCA, 1.13; CSQ, 1.05; TRD, 1.03; JCN, 0.90; and PLB, 0.94 (n ϭ 3-6). The phosphorylation state of PLB at Ser 16 was enhanced by isoproterenol in cardiomyocytes from both TG and WT mice (Fig. 3A).…”

Section: Resultsmentioning

confidence: 95%

“…Bands were detected using enhanced chemifluorescence (GE Healthcare, Munich, Germany) and a Storm PhosphorImager (GE Healthcare). The following primary antibodies were used: polyclonal rabbit anti 5-HT 4 receptor (Chemicon, Millipore), polyclonal rabbit anti calsequestrin (CSQ), monoclonal mouse anti-sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)2a, polyclonal rabbit anti-triadin (TRD), and polyclonal rabbit anti-junctin (JCN) (all kindly provided by L. R. Jones, Indianapolis, IN) as well as monoclonal mouse anti-PLB (A-1, Badrilla, Leeds, UK), polyclonal rabbit anti-phospho-PLB (antibodies were raised against PLB peptide phosphorylated at Ser 16 or at Thr 17 , Badrilla). Characteristics and use of these antibodies have been reported repeatedly by our group (e.g., Ref.…”

Section: Isolation Of 5-ht4a Receptor Cdna and Generation Of Transgenmentioning

confidence: 99%

“…The heart was excised under anesthesia and retrogradely perfused on a vertical Langendorff apparatus, and monophasic action potentials were recorded from the right atrial epicardium and LV epicardium as previously described (16,35). After an initial stabilization period, the intrinsic ventricular rhythm was observed after atrioventricular nodal block for 10 min to detect bradycardia-dependent arrhythmias.…”

Section: Isolation Of 5-ht4a Receptor Cdna and Generation Of Transgenmentioning

confidence: 99%

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Cardiac overexpression of the human 5-HT₄receptor in mice

Gergs¹,

Baumann²,

Böckler³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Serotonin (5-HT) exerts pleiotropic effects in the human cardiovascular system. Some of the effects are thought to be mediated via 5-HT4 receptors, which are expressed in the human atrium and in ventricular tissue. However, a true animal model to study these receptors in more detail has been hitherto lacking. Therefore, we generated, for the first time, a transgenic (TG) mouse with cardiac myocyte-specific expression of the human 5-HT4 receptor. RT-PCR and immunohistochemistry revealed expression of the receptor at the mRNA and protein levels. Stimulation of isolated cardiac preparations by isoproterenol increased phospholamban phosphorylation at Ser 16 and Thr 17 sites. 5-HT increased phosphorylation only in TG mice but not in wild-type (WT) mice. Furthermore, 5-HT increased contractility in isolated perfused hearts from TG mice but not WT mice. These effects of 5-HT could be blocked by the 5-HT 4 receptor-selective antagonist GR-125487. An intravenous infusion of 5-HT increased left ventricular contractility in TG mice but not in WT mice. Similarly, the increase in contractility by 5-HT in isolated cardiomyocytes from TG mice was accompanied by and probably mediated through an increase in L-type Ca 2ϩ channel current and in Ca 2ϩ transients. In intact animals, echocardiography revealed an inotropic and chronotropic effect of subcutaneously injected 5-HT in TG mice but not in WT mice. In isolated hearts from TG mice, spontaneous polymorphic atrial arrhythmias were noted. These findings demonstrate the functional expression of 5-HT4 receptors in the heart of TG mice, and a potential proarrhythmic effect in the atrium. Therefore, 5-HT4 receptorexpressing mice might be a useful model to mimic the human heart, where 5-HT 4 receptors are present and functional in the atrium and ventricle of the healthy and failing heart, and to investigate the influence of 5-HT in the development of cardiac arrhythmias and heart failure. serotonin; arrhythmia; transgenic mice; signal transduction MOST OF THE SEROTONIN (5-HT) in the blood originates from enterochromaffine cells of the gastrointestinal tract (53). 5-HT is released by these cells and is avidly taken up by platelets. Platelets seem to be the main source of 5-HT that influences the cardiovascular system. These influences include vasoconstriction, an increase in platelet aggregation, apoptosis of cardiac cells, augmentation in beating rate, the generation of arrhythmias (27), valvular heart disease (49), and positive inotropic and relaxant effects (for an overview, see Ref. 29).At present, seven groups of 5-HT-receptors have been distinguished (5-HT 1 -5-HT 7 ) (29). The 5-HT 4 receptor mediates the positive inotropic effect in humans (8,31,33,51). In the human atrium and ventricle, mRNAs of several splice variants of the 5-HT 4 receptor have been found (6, 2, 9).In isolated multicellular preparations from human atria, 5-HT exerts a positive inotropic effect and a relaxant (or lusitropic) effect (31, 33). These effects were accompanied by increases in cAMP content and ele...

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Section: Resultsmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 95%

Section: Isolation Of 5-ht4a Receptor Cdna and Generation Of Transgenmentioning

confidence: 99%

Section: Isolation Of 5-ht4a Receptor Cdna and Generation Of Transgenmentioning

confidence: 99%

See 2 more Smart Citations

Cardiac overexpression of the human 5-HT₄receptor in mice

Gergs¹,

Baumann²,

Böckler³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Selective A3R activation is cardioprotective in wildtype hearts and hearts over-expressing A1R, although A3R gene deletion generates an ischaemia-tolerant phenotype [529]. In a later study, it was shown that improved resistance of the heart to ischaemic damage can be achieved by increasing the expression of A3R, without detrimental side effects on heart rate or systolic function [530]. Reduced A3R transcription may contribute to improved ischaemia tolerance in aged hearts [531].…”

Section: Ischaemiamentioning

confidence: 99%

Cardiac purinergic signalling in health and disease

Burnstock

Pelleg

2014

Purinergic Signalling

120

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This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.

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