Disease relevance of Atp2a2

• SERCA2 was expressed in photoreceptor inner segments, amacrine and ganglion cells of the mouse retina [1].
• Patients with cardiac hypertrophy and heart failure display abnormally slowed myocardial relaxation, which is associated with downregulation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) gene expression [2].
• Overexpression of wtPKCepsilon and wtPKCdelta, but not wtPKCalpha, was sufficient to downregulate SERCA2 mRNA levels, as assessed by Northern blotting and quantitative, real-time RT-PCR (69 +/- 7 and 61 +/- 9% of control levels for wtPKCepsilon and wtPKCdelta, respectively; P < 0.05 for each adenovirus; n = 8 experiments) [2].
• Previous studies in adult myocytes isolated from rat hearts 3 wk after myocardial infarction (MI) demonstrated abnormal contractility and intracellular Ca(2+) concentration ([Ca(2+)](i)) homeostasis and decreased sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) expression and activity, but sarcoplasmic reticulum Ca(2+) leak was unchanged [3].
• We conclude that SERCA2 overexpression was only partially effective in ameliorating contraction and [Ca(2+)](i) transient abnormalities in our rat model of ischemic cardiomyopathy [3].

High impact information on Atp2a2

• The Ca2+ ATPase of the sarcoplasmic reticulum (SERCA2) plays a dominant role in lowering cytoplasmic calcium levels during cardiac relaxation and reduction of its activity has been linked to delayed diastolic relaxation in hypothyroid and failing hearts [4].
• Similar results were obtained for the contractile performance of myocytes isolated from a separate line (CJ2) of homozygous SERCA2 transgenic mice [4].
• To determine the contractile alterations resulting from increased SERCA2 expression, we generated transgenic mice overexpressing a rat SERCA2 transgene [4].
• Furthermore, cardiac function measured in vivo, demonstrated significantly accelerated contraction and relaxation in SERCA2 transgenic mice that were further augmented in both groups with isoproterenol administration [4].
• In isolated papillary muscle from SERCA2 transgenic mice, the time to half maximum postrest potentiation was significantly shorter than in negative littermates [4].

Chemical compound and disease context of Atp2a2

• Pressure-overload hypertrophy results in downregulation of the sarcoplasmic reticulum Ca(2+)-ATPase pump encoding SERCA2 gene that regulates Ca(2+) uptake and myocardial relaxation [5].
• Infection of such myocytes with a SERCA2 expressing adenovirus could reconstitute the Ca2+ transient, and augmented oxalate facilitated SERCA2 Ca2+ uptake [6].
• In aged rats, renovascular hypertension resulted in 100% mortality, probably related to elevated levels of circulating angiotensin II, whereas in adult rats, renovascular hypertension induced a mild LV hypertrophy associated with a selective alteration in SERCA2 gene expression [7].
• In the DOCA-salt-induced hypertrophy model, SERCA2 promoter activity was similar to that of sham controls [8].
• Phorbol myristate acetate-induced hypertrophy of neonatal rat cardiac myocytes is associated with decreased sarcoplasmic reticulum Ca2+ ATPase (SERCA2) gene expression and calcium reuptake [9].

Biological context of Atp2a2

• The goal of the current study was to investigate the efficacy of the RNAi method for ablation of PLB gene expression and restoration of Ca(2+) uptake function in cultured neonatal rat cardiac myocytes in which SERCA2 protein levels were decreased [10].
• METHODS: Primary cultures of neonatal rat ventricular myocytes were transiently transfected with luciferase (LUX) reporter gene constructs containing deletions of the SERCA2 promoter or which harbored mutations in consensus Sp1 transcription factor binding sites [11].
• Site-directed mutagenesis revealed that two Sp1 sites in the SERCA2 gene promoter region mediated the response to carvedilol under oxidative stress [12].
• The reduction of SERCA2 expression was associated with the up-regulation of transient receptor potential (TRP) channel proteins (TRPC4 and TRPC5) and Na+/Ca2+ exchanger, indicating that intracellular store deficiency was compensated for by Ca2+ fluxes through the plasma membrane [13].
• Pressure overload on the heart is known to produce hypertrophy of cardiomyocytes and distinct changes in protein phenotype, including reduced expression of the gene for the sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA2) [14].

Anatomical context of Atp2a2

• Remarkably, the SLN/(SERCA1 + SERCA2) mRNA ratio in normal cardiac muscle (0.96) was nearly the same as in diaphragm, but in EDL it amounted to only 0.05 that in diaphragm [15].
• Sarcoplasmic reticulum calcium cycling is determined in part by the ratio of SERCA2 to PLB [16].
• Thyroid hormone exerts positive inotropic effects on the heart mediated in part by its regulation of calcium transporter proteins, including sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2), phospholamban (PLB), and Na(+)/Ca(2+) exchanger (NCX) [16].
• Pulmonary trunk banding resulted in an induction of ANP mRNA, a moderate increase in collagenIII alpha1 mRNA and a decrease in SERCA2 and PLB mRNA levels in both the left and right ventricles, but changes were most pronounced in the myocardium surrounding the RV cavity [17].
• These results imply that the SERCA2 isoform controls Ca2+ sequestration into the endoplasmic reticulum in most classes of retinal neuron [1].

Associations of Atp2a2 with chemical compounds

• As a result the relative proportion of SERCA2 mRNA was increased from 43 +/- 7 % in control diaphragm to 52 +/- 4 % after triamcinolone treatment (P < 0.05) [15].
• In primary cultured neonatal rat cardiac myocytes, treatment with either carvedilol or its beta-receptor inactive metabolite, BM910228, attenuated the hydrogen peroxide-mediated decrease in SERCA2 mRNA and protein levels, while metoprolol, a pure beta-blocker, had no effect [12].
• This hypothesis predicts that improved SERCA2 function would provide protection from cardiotoxic effects of anthracycline administration [18].
• Doxorubicin was administered (1.7 mg/kg three times weekly; cumulative dose of 20 mg/kg) to 10 transgenic mice that overexpressed SERCA2 and to 10 isogenic littermates [18].
• In this study we have shown that the decrease in SERCA2 gene expression (normalized by poly(A)+ mRNA or 18 S rRNA) in rats with 8 wk of aortic constriction was prevented by treatment with etomoxir, an inhibitor of carnitine palmitoyltransferase 1 [14].

Regulatory relationships of Atp2a2

• Finally, PLB siRNA restored Ca(2+) uptake affinity following hydrogen peroxide-induced decreases in SERCA2 and PLB mRNA expression [10].
• Furthermore, we demonstrate that cotransfection of an Sp1 expression vector together with SERCA2-CAT constructs can up-regulate SERCA2 promoter activity [19].
• Endothelium from rat aorta expresses sarco/endoplasmic reticulum Ca2+(SERCA) pump gene SERCA3 where as the smooth muscle expresses SERCA2 [20].
• The antidiabetic agent rosiglitazone upregulates SERCA2 and enhances TNF-alpha- and LPS-induced NF-kappaB-dependent transcription and TNF-alpha-induced IL-6 secretion in ventricular myocytes [21].
• Leukemia Inhibitory Factor and Interleukin-6 downregulate sarcoplasmic reticulum Ca2+ ATPase (SERCA2) in cardiac myocytes [22].

Other interactions of Atp2a2

• This reduction was accounted for by a relatively larger decrease in the SERCA1 mRNA (-69 %, P < 0.05) whilst the decrease in SERCA2 mRNA (-49 %, P = 0.09) did not reach statistical significance [15].
• Similar beneficial effects of etomoxir treatment were also evident when the gene expression for SR SERCA2, PLP, and CRC in the hypertrophied heart was normalized with respect to mRNA for GAPDH [14].
• We investigated the expression of the SERCA2 and SERCA3 isozymes in PC12 cells exposed to agents interfering with different aspects of the posttranslational protein processing within the ER, thereby activating the ER stress-induced unfolded protein response (UPR) [23].
• Although beta-MHC and Kv1.5 mRNA content was returned to control levels, alpha-MHC and SERCA2 were unresponsive to T(3) at replacement doses, and only at higher doses of T(3) was alpha-MHC mRNA returned to control values [24].
• In this study, we investigated the effects of these cytokines (LIF & IL-6) on the regulation of SERCA2 levels in cardiac myocytes [22].

Analytical, diagnostic and therapeutic context of Atp2a2

• Atrial and left ventricular (LV) tissue homogenates were analyzed for expression of SERCA2, PLB, and NCX proteins by Western blot analysis [16].
• Analysis of distribution of SERCA2 immunofluorescence in the developing mouse retina revealed prominent SERCA2 signals throughout postnatal development [1].
• Denervation or TTX treatment prevented the expression of the SERCA2 isoform [25].
• We found, using RT-PCR with isoform-specific primers, that SERCA 2 and SERCA 3 mRNAs are co-expressed in human and rat islets of Langerhans and in the RINm5F beta-cell line [26].
• The intracellular Ca2+ system, which includes the ryanodine receptor 2 (RYR2), sarcoplasmic reticulum Ca2+-pump adenosine triphosphatase (SERCA2), and Ca2+-binding protein were quantitatively assayed by reverse-transcription polymerase chain reaction and Western blots and functionally by 3H-ryanodine binding and radiolabeled Ca2+ uptake [27].

References