Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation

Sood, Subeena; Chelu, Mihail G.; Oort, Ralph J. van; Skapura, Darlene G.; Santonastasi, Marco; Dobrev, Dobromir; Wehrens, Xander H.T.

doi:10.1016/j.hrthm.2008.03.030

Cited by 112 publications

(95 citation statements)

References 27 publications

(13 reference statements)

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“…Briefly, intracardiac electrograms were recorded using a 1.1F octapolar catheter (EPR-800; Millar Instruments) inserted via the right jugular vein. Atrial fibrillation (AF) inducibility was determined by previous protocol (48) and defined as overdriving pacing and defined as the occurrence of rapid and fragmented atrial electrograms with irregular AV-nodal conduction and ventricular rhythm for at least 1 s. Three pacing trials were applied in each mouse. Inducibility of AF was considered positive if at least two of three pacing trials induced AF.…”

Section: Methodsmentioning

confidence: 99%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3, that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility. irregular heart rate | single nucleotide variant | mouse genetics A trial fibrillation (AF), the most common arrhythmia in adult patients, increases in prevalence with age to almost 5% of the population over 65. Patients with AF have an increased risk of stroke, dementia, and heart failure (1). Electrical impulses that are critical for a coordinated, physiologic heartbeat originate in the sinoatrial node (SAN). In AF, abnormal fibrillatory atrial impulses override normal SAN function, with resultant irregular conduction to the ventricles. Many cases of ectopic electrical activity originate in the pulmonary vein (2). Other sites of ectopy include the left atrial posterior wall, superior vena cava, interatrial septum, crista terminalis, and coronary sinus myocardium (3, 4).Multiple approaches have been used to uncover genes that may contribute to the AF phenotype in adult patients. A seminal genome-wide association study (GWAS), subsequently replicated by multiple studies, uncovered a single nucleotide variant (SNV) on human 4q25 that was strongly associated with familial AF (5). Patients with the 4q25 variant exhibited early onset AF that was independent from other risk factors such as hypertension and diabetes, suggesting a novel biologic mechanism involving genes located on chromosome 4q25. The presence of the 4q25 SNV also had prognostic value because patients with the SNV are prone to cardioembolic str...

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Section: Methodsmentioning

confidence: 99%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Whereas most initial studies on the composition of the RyR2 protein complex were performed on ventricular myocardium, several recent studies suggest that atrial RyR2 are comprised of the same subunits and binding partners [19][20][21][22][23]. RyR2 are tetramers comprised of four RyR2 subunits, each of which associates with several regulatory subunits.…”

Section: Regulation Of Sr Ca 2+ Release In the Atriamentioning

confidence: 99%

“…Calmodulin (CaM) is an accessory protein that binds to and regulates RyR2 gating [24]. The FK506-binding protein (FKBP12.6, also known as calstabin2) stabilizes the RyR2 closed conformational state [20,25], and facilitates coupled gating between connected RyR2 channels [26]. Marx et al [18] demonstrated that protein kinase A (PKA) and protein phosphatases PP1 and PP2A bind to RyR2 via specific targeting molecules.…”

Section: Regulation Of Sr Ca 2+ Release In the Atriamentioning

confidence: 99%

“…For example, the level of the RyR2-stabilizing subunit FK506-binding protein (FKBP12.6, calstabin2) was reduced by about 50% in patients with chronic AF, which could explain why RyR2 channels fail to remain closed during diastole [21]. Interestingly, mice deficient in FKBP12.6 exhibit an increased vulnerability to pacinginduced AF and enhanced spontaneous SR Ca 2+ leak [20]. Reduced CSQ2 levels may also contribute to SR dysfunction in AF [78].…”

Section: Enhanced Ryr2 Activity In Afmentioning

confidence: 99%

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Role of abnormal sarcoplasmic reticulum function in atrial fibrillation

Wehrens¹,

Ather²,

Dobrev³

2010

Therapy

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SummaryAtrial fibrillation (AF) is the most common cardiac arrhythmia, and is a cause of significant morbidity and mortality if left untreated. AF has been associated with profound changes in sarcoplasmic reticulum Ca 2+ homeostasis, which might contribute to both reduced contractile function and increased arrhythmogenesis in atria. Studies in human tissue samples and various animal models of AF have revealed changes in both expression levels and posttranslational modifications of key Ca 2+ handling proteins, which may contribute to arrhythmogenesis. In this review, we will focus on the molecular basis of alterations in sarcoplasmic reticulum Ca 2+ handling in AF and their potential therapeutic implications.

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“…Transgenic and gene targeting methods can be used to generate mice with altered cardiac size and function, [1][2][3] and as a result, in vivo techniques are needed to evaluate their cardiac phenotype. Transthoracic echocardiography, pulse wave Doppler (PWD), and tissue Doppler imaging (TDI) can be used to provide dimensional measurements of the mouse heart and to quantify the degree of cardiac systolic and diastolic performance.…”

Section: Introductionmentioning

confidence: 99%

Transthoracic Echocardiography in Mice

Respress

Wehrens

2010

JoVE

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In recent years, murine models have become the primary avenue for studying the molecular mechanisms of cardiac dysfunction resulting from changes in gene expression. Transgenic and gene targeting methods can be used to generate mice with altered cardiac size and function, 1-3 and as a result, in vivo techniques are needed to evaluate their cardiac phenotype. Transthoracic echocardiography, pulse wave Doppler (PWD), and tissue Doppler imaging (TDI) can be used to provide dimensional measurements of the mouse heart and to quantify the degree of cardiac systolic and diastolic performance. Two-dimensional imaging is used to detect abnormal anatomy or movements of the left ventricle, whereas M-mode echo is used for quantification of cardiac dimensions and contractility. 4,5 In addition, PWD is used to quantify localized velocity of turbulent flow, whereas TDI is used to measure the velocity of myocardial motion. 7 Thus, transthoracic echocardiography offers a comprehensive method for the noninvasive evaluation of cardiac function in mice. Video LinkThe video component of this article can be found at http://www.jove.com/video/1738/ Protocol Preparing Mice for Imaging Studies1. Prior to the imaging studies, anesthetize the mouse (2% isoflurane mixed with 0.5 L/min 100% O 2 )in the induction chamber. Be sure to filter waste gas for the safety of the operator. Remove the animal from the induction chamber and use hair clippers to shave the fur from the neckline to mid chest level. Then remove the remaining body hair with hair removal cream. This preparation may be performed a day prior to imaging studies to minimize potential undesired stress responses in the mice. 2. Apply duralube gel to both eyes to prevent drying of the sclera (avoid contacting the cornea with the gel applicator). Place the anesthetized mouse in a supine position atop a heating pad with embedded ECG leads in order to maintain body temperature. 3. Place the snout within a nose cone connected to the anesthesia system to maintain a steady-state sedation level throughout the procedure (1.0% to 1.5% isoflurane mixed with 0.5 L/min 100% O 2 ). Perform a toe or tail pinch to confirm sedation. If necessary, the level of anesthesia can be adjusted to obtain a target heart rate of 450 ± 50 beats per minute (bpm). 4. Gently insert a rectal probe (after lubricating) to continuously monitor and adjust body temperature via the heating pad. It is important to maintain the body temperature within a narrow range (37.0 °C ± 0.5 °C), as even moderate changes in temperature and heart rate affect cardiac function in mice. 5. Apply electrode gel to the four paws and tape them to the ECG electrodes. Evaluating Systolic Function of the Heart1. To begin this procedure, apply a layer of preheated ultrasound gel to the chest, primarily the area overlying the heart. Gel should be warmed to approximate body temperature. A volume of cold gel may rapidly add to the rate of body temperature loss. Avoid air bubbles in the gel, which can interfere with ultrasonic imaging. 2. I...

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Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation

Cited by 112 publications

References 27 publications

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Role of abnormal sarcoplasmic reticulum function in atrial fibrillation

Transthoracic Echocardiography in Mice

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