Regulation of sarco(endo)plasmic reticulum Ca²⁺-ATPase and calsequestrin gene expression in the heart

Abstract

<jats:p>The precise control of Ca<jats:sup>2+</jats:sup>levels during the contraction–relaxation cycle in cardiac myocytes is extremely important for normal beat-to-beat contractile activity. The sarcoplasmic reticulum (SR) plays a key role controlling calcium concentration in the cytosol. The SR Ca<jats:sup>2+</jats:sup>-ATPase (SERCA2) transports Ca<jats:sup>2+</jats:sup>inside the SR lumen during relaxation of the cardiac myocyte. Calsequestrin (Casq2) is the main protein in the SR lumen, functioning as a Ca<jats:sup>2+</jats:sup>buffer and participating in Ca<jats:sup>2+</jats:sup>release by interacting with the ryanodine receptor 2 (RyR2) Ca<jats:sup>2+</jats:sup>-release channel. Alterations in normal Ca<jats:sup>2+</jats:sup>handling significantly contribute to the contractile dysfunction observed in cardiac hypertrophy and in heart failure. Transcriptional regulation of the SERCA2 gene has been extensively studied and some of the mechanisms regulating its expression have been elucidated. Overexpression of Sp1 factor in cardiac hypertrophy downregulates SERCA2 gene expression and increased levels of thyroid hormone up-regulates its transcription. Other hormones such norepinephrine, angiotensin II, endothelin-1, parathyroid hormone, prostaglandin-F2α, as well the cytokines tumor necrosis factor-α and interleukin-6 also downregulate SERCA2 expression. Calcium acting through the calcineurin–NFAT (nuclear factor of activated T cells) pathway has been suggested to regulate SERCA2 and CASQ2 gene expression. This review focuses on the current knowledge regarding transcriptional regulation of SERCA2 and CASQ2 genes in the normal and pathologic heart.</jats:p>

Cardiomyocyte-specific expression of CRNK, the C-terminal domain of PYK2, maintains ventricular function and slows ventricular remodeling in a mouse model of dilated cardiomyopathy

“…Reduced SERCA2 gene expression is frequently observed in experimental animal models and patients with end-stage HF [37], but its role in the initial stages of LV remodeling and HF progression remains unclear. For instance, Periasamy and colleagues [38,39] have shown that cardiomyocytes isolated from heterozygous SERCA2 knockout mice have a ~35% reduction in SERCA2 protein, a 30-40% reduction in the amplitude of the cytosolic Ca 2+ transient, and a 40 60% reduction in SR Ca 2+ load.…”

The Sarcoplasmic Reticulum and the Evolution of the Vertebrate Heart

“…RyR modulation from the SR lumen is achieved via triadin and junctin, which form complexes with calsequestrin (14,56,57,86). Calsequestrin is the most abundant Ca 2ϩ binding protein in the SR (9,160). CSQ2 (the mammalian cardiac isoform) binds Ca 2ϩ with a high capacity (ϳ60 -80 mol Ca 2ϩ /mol CSQ2) and a moderate affinity [dissociation constant (k d ) of ϳ1 mM] (109), thereby buffering SR Ca 2ϩ .…”

AAV-mediated gene therapy for heart failure: enhancing contractility and calcium handling

“…The rise in sarcoplasmic calcium causes contraction by Ca 2+ binding to troponin C, which relieves constraints on actin-myosin interaction and cross-bridge formation. With relaxation, 60%–80% of the sarcoplasmic Ca 2+ is actively transported into the sarcoplasmic reticulum lumen by the sarco(endo)plasmic reticulum Ca 2+ -ATPase pump (SERCA2a), while the remainder exits the cardiac myocyte by way of the Na + -Ca 2+ exchanger [7]. With heart failure, Ca 2+ uptake into the sarcoplasmic reticulum is impaired due to decreased expression of SERCA2a [7].…”

“…With relaxation, 60%–80% of the sarcoplasmic Ca 2+ is actively transported into the sarcoplasmic reticulum lumen by the sarco(endo)plasmic reticulum Ca 2+ -ATPase pump (SERCA2a), while the remainder exits the cardiac myocyte by way of the Na + -Ca 2+ exchanger [7]. With heart failure, Ca 2+ uptake into the sarcoplasmic reticulum is impaired due to decreased expression of SERCA2a [7]. Activity of SERCA2a is decreased as well, due to an increased association of SERCA2a with its inhibitory regulator phospholamban for two reasons: first, normally, phosphorylation of phospholamban relieves SERCA2a inhibition by causing its dissociation from SERCA2a, but, in heart failure, there is less phosphorylation of phospholamban due to increased protein phosphatase 1 (PP1) activity [8]; second, the decreased SERCA2a/phospholamban ratio means that there is more phospholamban relative to SERCA2a, thus favoring SERCA2a inhibition.…”

“…In addition, the sarcoplasmic reticulum becomes leaky in heart failure due to CaMKII-dependent phosphorylation of RyR2 [9]. Thus, in the failing heart, the sarcoplasmic reticulum does not function as well in removing Ca 2+ from the sarcoplasm, which has two consequences: (1) there is an increase in resting sarcoplasmic Ca 2+ that contributes to reduced relaxation and diastolic dysfunction; and (2) there is less Ca 2+ released from the sarcoplasmic reticulum during contraction, which means that the force of contraction is reduced [7]. Strategies to improve or restore sarcoplasmic reticulum function would be predicted to reverse heart failure.…”