Van Eyk, Dunn - Proteomic and Genomic Analysis of Cardiovascular Disease - 2003 (522919), страница 31
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Am. J. Physiol. Heart Circ.Physiol. 2000, 279, H451–H456.Silverman, G., Bird, P., Carrell, R.,Church, F., Coughlin, P., Gettins, P.,Irving, J., Lomas, D., Luke, C., Moyer,R., Pemberton, P., Remold-O’Donnell,E., Salvesen, G., Travis, J., Whisstock,J. The serpins are an expanding superfamily of structurally similar but functionnally diverse proteins. J. Biol. Chem.2001, 276, 33293–33296.996DNA Microarray Gene Profiling:A Tool for the Elucidation of Cardioprotective GenesElizabeth Murphy, Cynthia A. Afshari, John G.
Petranka,and Charles Steenbergen6.1IntroductionThis review will address several issues regarding the use of cDNA microarray geneprofiling to identify cardioprotective genes. Section 1 will review data in the literature suggesting that there are cardioprotective genes that can be upregulated to protect the myocardium.
This section also will discuss how these cardioprotective genesmight lead to protection. Section 2 will consider whether different cardioprotectivemechanisms act via induction of common genes. For example, are preconditioningand protection in females mediated via similar changes in gene expression? One ofthe primary rationales for identifying cardioprotective genes is to enhance expression of these genes to elicit cardioprotection. Thus it is important to understandthe consequences of long-term activation of these genes.
This issue will be discussed briefly in section 3. Section 3 also will consider the role of the level of geneexpression. For example, it has been shown that high levels of expression of proteinkinase C-epsilon (PKC-e) lead to hypertrophy, whereas low or moderate levels of expression lead to cardioprotection. Section 4 will discuss possible strategies to identifythese cardioprotective genes, and section 5 will discuss practical considerations inthe use of microarray gene profiling to identify cardioprotective genes.6.2Candidates for Cardioprotective Genes and Possible Mechanism(s) of Protection6.2.1Candidate Genes Involved in CardioprotectionCardioprotection can be induced by intermittent stress such as preconditioning, orby addition of agonists which stimulate signaling pathways involved in preconditioning [1].
Another related means of studying cardioprotection and/or preconditioning is to modify candidate genes using transgenic approaches. In addition topreconditioning, endogenous protection is reported in females. We will considercandidate cardioprotective genes from all these approaches.Proteomic and Genomic Analysis of Cardiovascular Disease.Edited by Jennifer E.
van Eyk, Michael J. DunnCopyright © 2003 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-30596-31006 DNA Microarray Gene ProfilingPreconditioning, with brief intermittent periods of ischemia and reperfusion,has been shown to induce protection against injury during a subsequent sustained period of ischemia [1].
The sustained period of ischemia may occur shortlyafter the preconditioning stimulus (acute preconditioning) or 1–3 days later (delayed preconditioning). It has been reported that acute preconditioning does notrequire new gene synthesis [2], whereas delayed preconditioning is dependent onnew transcription and translation. Delayed preconditioning is reminiscent ofother types of stress-induced protection such as the classic heat shock response.In addition to intermittent ischemia, preconditioning can be induced by a varietyof stressors such as osmotic stress, redox stress, heat shock, high calcium, andtoxins such as monophosphoryllipid A. These data are consistent with the hypothesis that stress-induced signaling pathways enhance transcription of genes thatlead to cardioprotection. However, since acute preconditioning occurs within minutes and is reported to occur without new gene transcription, it appears that posttranscriptional changes in signaling pathways can also have a major role in cardioprotection and such changes may not be elucidated by gene profiling.Regarding changes in gene expression that lead to cardioprotection, Schaperand coworkers have reported that brief ischemia and reperfusion, similar to thepreconditioning trigger, induce transcription of many genes [3].
They found increased expression of mRNA for immediate-early genes (fos, junB, rgr-1), heatshock protein 27 (HSP27), genes involved in calcium-handling (Ca-ATPase, calsequestrin, phospholamban), and growth factors. However, in this study, there wasno assessment of whether these changes in gene expression were causally involved in protection.Many cardioprotective gene products have been identified using inhibitors toblock preconditioning, or activators to mimic preconditioning. Transgenic animalshave also been used to implicate specific genes involved in preconditioning. Bolliand coworkers have shown that mice lacking inducible nitric oxide synthase(iNOS) did not exhibit delayed preconditioning, suggesting an important role foriNOS in delayed preconditioning [4].
Bolli and coworkers further showed that selective inhibitors of cyclooxygenase-2 (COX-2) blocked delayed preconditioning [5].As nuclear factor-kappaB (NF-jB) enhances transcription of COX-2 and iNOS,Bolli and coworkers also examined the role of the transcription factor NF-jB inpreconditioning. An inhibitor of NF-jB blocked the preconditioning induced nuclear translocation of NF-jB and concomitantly blocked cardioprotection [6]. Anew mouse model with cardiac specific expression of a mutant I-jB-alpha shouldprovide further information on the role of NF-jB in cardioprotection [7].
In contrast to iNOS, the results of studies to examine the role for endothelial nitric oxide synthase (eNOS) in cardioprotection are mixed. Most studies report that nitricoxide donors are cardioprotective, and hearts from mice null for eNOS have beenreported to have increased infarct size compared to wild-type (WT) littermates [8].However, another study found no difference in infarct size between eNOS nullhearts and WT hearts, but they did find that acute preconditioning was blocked ineNOS-knockout (KO) hearts using 2 or 3 cycles of preconditioning, but was notblocked if 4 cycles of preconditioning were employed [9]. Delayed preconditioning6.2 Candidates for Cardioprotective Genes and Possible Mechanism(s) of Protectionwas not studied in these eNOS-KO mice.
eNOS-KO hearts have been reported tohave increased induction of iNOS during ischemia and this may complicate theresults [10]. Hearts from mice null for neuronal nitric oxide synthase (nNOS) hadinfarcts that were similar in size to those in WT littermates [11].Several investigators, using inhibitors and transgenic mouse models haveshown a convincing role for PKC-e in cardioprotection [12–14]. Interestingly, adose-dependent effect of PKC-e overexpression was observed [12]. Low to moderate cardiac specific overexpression of PKC-e confered reduced susceptibility toischemic injury [12, 14]. However, high levels of overexpression of PKC-e resultedin cardiac hypertrophy [15]. Lck, a src family tyrosine kinase, has been shown toco-precipitate with PKC-e, and Lck-KO hearts did not exhibit preconditioning [16].Cardiac specific overexpression of the A1-adenosine receptor [17, 18], and the A3adenosine receptor [19] also were reported to be cardioprotective.
Bradykinin B2receptor knock-out mice were not protected by acute preconditioning [20]. Cardiacspecific overexpression of insulin-like growth factor-1 (IGF-1) [21], or fibroblastgrowth factor-2 (FGF-2) were also cardioprotective [22].A number of stress-related genes have also been shown to be important in cardioprotection. Overexpression of heat shock protein 70 (HSP 70) was cardioprotective [23], as was overexpression of Cu/Zn superoxide dismutase (SOD) [24, 25] aswell as overexpression of MnSOD [26]. Futhermore, Cu/Zn SOD null mice hadincreased infarcts following ischemia-reperfusion [27]. Two recent studies suggestan important role for heme-oxygenase-1 (HO-1) in cardioprotection.
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