SummaryThe cytosolic calcium concentration ([Ca 21 ] c ) is key for the regulation of many cellular processes, such cell signaling and proliferation, metabolism, and muscle contraction. In cardiomyocytes, Ca 21 is an important regulator in many cellular functions such electrophysiological processes, excitation-contraction coupling, regulation of contractile proteins activity, energy metabolism, cell death, and transcriptional regulation by the activation of Ca 21 -dependent transcriptional pathways.

The precise control of Ca2+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 Ca2+-ATPase (SERCA2) transports Ca2+inside the SR lumen during relaxation of the cardiac myocyte. Calsequestrin (Casq2) is the main protein in the SR lumen, functioning as a Ca2+buffer and participating in Ca2+release by interacting with the ryanodine receptor 2 (RyR2) Ca2+-release channel. Alterations in normal Ca2+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.

Lovastatin modifies the mevalonate pathway without affecting cholesterol levels in vivo and is able to reduce Aβ levels only in vitro.

Abstract:The complexity of heart physiology has delayed the implementation of efficient, feasible, and safe therapies to fight against heart diseases for many years. As knowledge of the precise mechanisms governing cardiac hypertrophy and heart failure development increases, the availability of new therapeutic alternatives also grows. Since the cardiomyocyte physiology deeply depends on the correct calcium handling, many efforts to describe accurately the excitation-contraction coupling process in the heart and the proteins involved have been made. Among the proteins participating in calcium handling, sarco/endoplasmic reticulum Ca 2+ adenosine triphosphatase-2a (SERCA2a), whose expression and function is decreased in heart failure, stands out because of its critical role regulating Ca 2+ concentration in the cardiomyocyte. The importance of SERCA2a has been reflected in numerous studies aimed to describe its expression and function. Recently, gene therapy to deliver SERCA2a has shown promising results in human clinical trials. This paper reviews the current literature knowledge exploring diverse approaches to rescue SERCA2a expression in heart failure. It also discusses some data suggesting other possible therapies that could improve SERCA2a expression and function in cardiac diseases.

The cardiac sarco/endoplasmic reticulum Ca-ATPase-2a (SERCA2a) is vital for the correct handling of calcium concentration in cardiomyocytes. Recent studies showed that the induction of endoplasmic reticulum (ER) stress (ERS) with the SERCA2 inhibitor Thapsigargin (Tg) increases the mRNA and protein levels of SERCA2a. The SERCA2 gene promoter contains an ERS response element (ERSE) at position -78 bp that is conserved among species and might transcriptionally regulate SERCA2 gene expression. However, its involvement in SERCA2 basal and calcium-mediated transcriptional activation has not been elucidated. In this work, we show that in cellular cultures of neonatal rat ventricular myocytes, the treatment with Tg or the calcium ionophore A23187 increases the SERCA2a mRNA and protein abundance, as well as the transcriptional activity of two chimeric human SERCA2 gene constructs, containing -254 and -2579 bp of 5'-regulatory region cloned in the pGL3-basic vector and transiently transfected in cultured cardiomyocytes. We found that the ERSE present in the SERCA2 proximal promoter contains a CCAAT box that is involved in basal and ERS-mediated hSERCA2 transcriptional activation. The EMSA results showed that the CCAAT box present in the ERSE recruits the NF-Y transcription factor. Additionally, by ChIP assays, we confirmed in vivo binding of NF-Y and C/EBPβ transcription factors to the SERCA2 gene proximal promoter.