Elevated InsP₃R expression underlies enhanced calcium fluxes and spontaneous extra-systolic calcium release events in hypertrophic cardiac myocytes

Mutual antagonism between IP3RII and miRNA-133a regulates calcium signals and cardiac hypertrophy

“…Consistent with this hypothesis, miRNA expression is altered in a diagnostic manner in left ventricular samples taken from humans suffering from a variety of cardiac pathologies (Ikeda et al, 2007) and in mouse models of hypertrophic remodeling (van Rooij et al, 2006). More specifically, miRNAs including miR-1 (Sayed et al, 2007;Li et al, 2010b), miR-133a (Carè et al, 2007), This result is in concordance with the observation that IP 3 RII protein expression is unaltered in noncardiomyocytes under hypertrophic conditions (Harzheim et al, 2010), suggesting that miR-133a and IP 3 RII expression levels may be inversely correlated. The genomic sequence encoding miR-133a is clustered bi-cistronically with the sequence for another muscle-specific miRNA, miR-1.…”

“…1,c and d). Our previous observations have demonstrated an increase in IP 3 RII protein expression that is restricted to the cardiomyocytes of the hypertrophic heart (Harzheim et al, 2009(Harzheim et al, , 2010. This response is not recapitulated in the noncardiomyocyte population, which expresses negligible amounts of IP 3 RII protein under both control (Perez et al, 1997;Harzheim et al, 2010) and hypertrophic conditions (Harzheim et al, 2009(Harzheim et al, , 2010.…”

“…For example, adult ventricular myocytes express low levels of the inositol 1,4,5-triphosphate II (IP 3 RII) calcium channel within the membranes of the sarcoplasmic and perinuclear calcium stores at baseline (Lipp et al, 2000;Guatimosim et al, 2008;Luo et al, 2008;Higazi et al, 2009). However, in failing human myocardium and cardiomyocytes from genetic and experimentally induced animal models of hypertrophy, IP 3 RII levels are increased (Harzheim et al, 2009(Harzheim et al, , 2010Nakayama et al, 2010). Under these conditions, IP 3 -induced calcium release (IICR) from IP 3 RII has deleterious effects on cellular function.…”

Signaling in Muscle Contraction

“…This has a lower ATPase activity and a lower rate of contraction. Other changes include increased SERCA2A activity (Hasenfuss et al 1994;Meyer et al 1995), up-regulation of IP 3 R2 (Harzheim et al 2010), and changes to a neuronal calcium sensor (NCS1). NCS1 is a calcium-binding protein that also interacts with IP 3 R (Schlecker et al 2006).…”

Calcineurin-NFATc Regulates Type 2 Inositol 1,4,5-Trisphosphate Receptor (InsP3R2) Expression during Cardiac Remodeling

“…Additionally, InsP 3 R2-mediated Ca 2ϩ release is instrumental in excitation-transcription coupling to activate hypertrophic gene expression by modulating CaMKII␦, histone deacetylase, and calcineurin-NFATc signaling pathways (12,13,16). 4 Recent studies have shown that there was an elevated expression of InsP 3 R2 in human and animal heart failure models (20,21). Nevertheless, the molecular mechanism that regulates the expression of InsP 3 R2 in cardiac myocytes is not well understood.…”