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

Abstract

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...

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

“…Cre mice has been reported previously (Cobb et al, 2006;Moses et al, 2001;Stanley et al, 2002;Sun et al, 2013;Wang et al, 2014a;Yu et al, 2005). The Tulane University Institutional Animal Care and Use Committee approved the animal experiments in this study.…”

“…To comprehensively document the Shox2 expression pattern in the developing heart, we created a knock-in allele (Shox2 HA ) that harbors a FLAG-HA-tagged Shox2a isoform coupled with IRESDsRed sequences (Wang et al, 2014a). Using this allele, which allows for live imaging of Shox2 expression, we found a wide but specific Shox2 expression domain in the developing venous pole ( Fig.…”

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

“…5.1) [62,65,66]. Jako potencjalne mechanizmy leżące u podłoża zwiększonego ryzyka AF u nosicieli częstych wariantów genetycznych postuluje się zmiany charakterystyki potencjału czynnościowego komórek przedsionków [67][68][69][70], przebudowę przedsionków oraz zmodyfikowaną penetrację rzadkich defektów genetycznych [61]. Warianty genetyczne mogłyby w przyszłości stać się użyteczne podczas doboru pacjentów do strategii kontroli rytmu serca lub kontroli częstości rytmu komór [71][72][73][74].…”

A unique stylopod patterning mechanism by Shox2 controlled osteogenesis

“…Flox , Col2a1-Cre and Col3.6-Cre alleles used in this study were described previously (Cobb et al, 2006;Liu et al, 2004;Ovchinnikov et al, 2000;Sun et al, 2013;Wang et al, 2014;Ye et al, 2015b;Yu et al, 2005). The animal experiments in this study were approved by The Tulane University Institutional Animal Care and Use Committee.…”