Abstract
In animal models of conotruncal heart defects, an abnormal calcium sensitivity of the contractile apparatus and a depressed L-type calcium current have been described. Sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA) is a membrane protein that catalyzes the ATP-dependent transport of Ca(2+) from the cytosol to the SR. The activity of SERCA is inhibited by phospholamban (PLN) and sarcolipin (SLN), and all these proteins participate in maintaining the normal intracellular calcium handling. Ryanodine receptors (RyRs) are the major SR calcium-release channels required for excitation-contraction coupling in skeletal and cardiac muscle. Our objective was to evaluate SERCA2a (i.e., the SERCA cardiac isoform), PLN, SLN, and RyR2 (i.e., the RyR isoform enriched in the heart) gene expression in myocardial tissue of patients affected by tetralogy of Fallot (TOF), a conotruncal heart defect. The gene expression of target genes was assessed semiquantitatively by RT-PCR using the calsequestrin (CASQ, a housekeeping gene) RNA as internal standard in the atrial myocardium of 23 pediatric patients undergoing surgical correction of TOF, in 10 age-matched patients with ventricular septal defect (VSD) and in 13 age-matched children with atrial septal defect (ASD). We observed a significantly lower expression of PLN and SLN in TOF patients, while there was no difference between the expression of SERCA2a and RyR2 in TOF and VSD. These data suggest a complex mechanism aimed to enhance the intracellular Ca(2+) reserve in children affected by tetralogy of Fallot.
Highlights
Human conotruncal heart defects are congenital heart defects (CHD) affecting the cardiac outflow, including the muscularized conus and the adjacent truncus arteriosus, collectively termed the conotruncus [1]
To clarify the relationship between congenital heart defects (CHD) and myocardial calcium handling in humans, we evaluated SERCA2a, RyR2, PLN, and SLN gene expressions in children with tetralogy of Fallot (TOF), a conotruncal defect, as well as in those affected by ventricular septal defects (VSD) and atrial septal defects (ASD), which are non-conotruncal malformations
We found a statistically significant difference by comparing values of SERCA2a gene expression in ASD with whole values obtained from TOF and VSD patients (0.54±0.06) (Figure 1)
Summary
Human conotruncal heart defects are congenital heart defects (CHD) affecting the cardiac outflow, including the muscularized conus and the adjacent truncus arteriosus, collectively termed the conotruncus [1]. Frequent conotruncal defects are tetralogy of Fallot (TOF), interrupted aortic arch, transposition of the great arteries, double-outlet right ventricle, persistent truncus arteriosus, and aortic arch anomalies [2]. A specific neural cell crest population, named cardiac neural crest, is responsible for the morphogenesis of the outflow region of the developing heart [3] and conotruncal heart defects are due to alterations in the neural crest (NC) migration [2]. Animal models of conotruncal defects were created by NC ablation, providing a powerful model of cardiovascular dysmorphogenesis [5]. The function of RyR2 (the cardiac isoform) is to allow the calcium-induced calcium release that brings about contraction, while myocyte relaxation results in RyR2 closure accompanied by the Ca2+ re-uptake into SR through the SR Ca2+/ ATPase pump (SERCA) [8]. Unphosphorylated PLN inhibits SERCA2a by lowering both its apparent Ca2+ affinity and SLN regulates SERCA2a by lowering Ca2+ affinity and reducing Vmax, as well as by inducing a super-inhibitory effect of PLN to SERCA2a [8]
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