Replacement of the Muscle-Specific Sarcoplasmic Reticulum Ca ²⁺ -ATPase Isoform SERCA2a by the Nonmuscle SERCA2b Homologue Causes Mild Concentric Hypertrophy and Impairs Contraction-Relaxation of the Heart

Abstract

The cardiac sarco(endo)plasmic reticulum Ca(2+)-ATPase gene (ATP2A2) encodes the following two different protein isoforms: SERCA2a (muscle-specific) and SERCA2b (ubiquitous). We have investigated whether this isoform specificity is required for normal cardiac function. Gene targeting in mice successfully disrupted the splicing mechanism responsible for generating the SERCA2a isoform. Homozygous SERCA2a(-/-) mice displayed a complete loss of SERCA2a mRNA and protein resulting in a switch to the SERCA2b isoform. The expression of SERCA2b mRNA and protein in hearts of SERCA2a(-/-) mice corresponded to only 50% of wild-type SERCA2 levels. Cardiac phospholamban mRNA levels were unaltered in SERCA2a(-/-) mice, but total phospholamban protein levels increased 2-fold. The transgenic phenotype was characterized by a approximately 20% increase in embryonic and neonatal mortality (early phenotype), with histopathologic evidence of major cardiac malformations. Adult SERCA2a(-/-) animals (adult phenotype) showed a reduced spontaneous nocturnal activity and developed a mild compensatory concentric cardiac hypertrophy with impaired cardiac contractility and relaxation, but preserved beta-adrenergic response. Ca(2+) uptake levels in SERCA2a(-/-) cardiac homogenates were reduced by approximately 50%. In isolated cells, relaxation and Ca(2+) removal by the SR were significantly reduced. Comparison of our data with those obtained in mice expressing similar cardiac levels of SERCA2a instead of SERCA2b indicate the importance of the muscle-specific SERCA2a isoform for normal cardiac development and for the cardiac contraction-relaxation cycle.

The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

“…The idea that SERCA2a expression might protect against cell proliferation, originated from studies where heterozygous mice with a null mutation in the SERCA2 gene develop cancers of the skin and the upper digestive tract [85], as well as cardiac hypertrophy [107]. Additional studies showed that mice in which SERCA2a has been replaced by SERCA2b develop dilated cardiac hypertrophy [144]. In contrast, cardiacspecific expression of SERCA2a in transgenic animals showed improved contractile function under basal conditions and pressure overload [94].…”

Sarco/Endoplasmic Reticulum Ca 2+ -ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat

“…PI3K-or Gq/11-coupled receptor agonists, known to be mitogenic factors, induce NFAT-dependent transcriptional activation in vascular myocytes. 6,7,14 -16 Several previous studies have suggested that SERCA2a is involved in the control of proliferation and growth: transgenic mice with only one allele of the ATP2a2 gene (SERCA2) develop numerous cancers of the upper digestive tract and skin, and cardiac hypertrophy 17,18 ; low levels of SERCA2a are associated with cardiac hypertrophy both in humans and animals 19 -21 ; mice in which SERCA2a has been replaced by SERCA2b develop cardiac hypertrophy 22 ; finally, loss of SERCA2a is associated with VSMC proliferation. 7,9 Similarly, only SERCA2b is present in proliferating BC3H1 muscle cells whereas SERCA1, SERCA2a, and SERCA2b are present in quiescent differentiated BC3H1 muscle cells.…”

MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development

“…During the development of embryonic muscle and repair of adult muscle injury, alternative splicing plays a critical role in the establishment of the mature pattern of muscle gene expression, including definition of the excitatory-contractile apparatus unique to a particular muscle type (Morano 2003;Agarkova and Perriard 2005). Various myopathies caused by aberrant splicing underscore its importance in myogenesis (Ver Heyen et al 2001;Faustino and Cooper 2003;Day and Ranum 2005;Ladd et al 2005).…”