Subramanian Meenakumari, Hunt Adam L, Petrucci Giuseppe A, Chen Zengyi, Hendley Edith D, Palmer Bradley M
Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, United States.
Department of Chemistry, University of Vermont, Burlington, VT 05405, United States.
J Trace Elem Med Biol. 2014 Jul;28(3):311-6. doi: 10.1016/j.jtemb.2014.02.002. Epub 2014 Feb 22.
The spontaneously hypertensive rat (SHR) has been studied extensively as a model of left ventricular hypertrophy (LVH) and associated cardiac dysfunction due to hypertension (HT). The SHR also possesses a hyperactive trait (HA). Crossbreeding SHR with Wistar-Kyoto (WKY) control rats, which are nonHT and nonHA, followed by selected inbreeding produced two additional homozygous strains: WKHT and WKHA, in which the traits of HT and HA, respectively, are expressed separately. WKHT, WKHA and SHR all display LVH, but only the SHR exhibits cardiac dysfunction. We hypothesized that cardiac dysfunction in the SHR is uniquely characterized by calcium overload. We measured total cardiac Ca, Cu, Fe, K, Mg and Zn in the four strains. We found elevated Ca and depressed Cu, Mg and Zn with HT, but not unique to SHR. We surmise that HT promotes aberrant regulation of cardiac Ca(2+), Cu(2+), Mg(2+) and Zn(2+), which does not necessarily result in cardiac dysfunction. Interestingly, Cu was elevated in HA strains compared to nonHA counterparts. We then analyzed gene expression as mRNA of Cu-containing proteins, most notably mitochondrial-Cox, Dbh, Lox, Loxl1, Loxl2, Sod1 and Tyr. The gene expression profiles of Lox, Loxl1, Loxl2 and Sod1 were found especially high in the WKHA, which if reflective of protein content could account for the high Cu content in the WKHA. The mRNA of other genes, notably Mb, Fxyd1, Maoa and Maob were also examined. We found that Maoa gene expression and monoamine oxidase-A (MAO-A) protein content were low in the SHR compared to the other strains. The finding that MAO-A protein is low in the SHR and normal in the WKHT and WKHA strains is most consistent with the idea that MAO-A protects against the development of cardiac dysfunction in LVH but not against LVH in these rats.
自发性高血压大鼠（SHR）作为左心室肥厚（LVH）以及因高血压（HT）导致的相关心脏功能障碍的模型，已得到广泛研究。SHR还具有多动特质（HA）。将SHR与非高血压且无多动特质的Wistar - Kyoto（WKY）对照大鼠杂交，随后进行选择性近亲繁殖，产生了另外两个纯合品系：WKHT和WKHA，其中HT和HA特质分别单独表达。WKHT、WKHA和SHR均表现出LVH，但只有SHR出现心脏功能障碍。我们推测SHR中的心脏功能障碍具有钙超载的独特特征。我们测量了这四个品系心脏中的总钙、铜、铁、钾、镁和锌含量。我们发现随着高血压的出现，钙含量升高，铜、镁和锌含量降低，但这并非SHR所特有。我们推测高血压促进了心脏钙（2 +）、铜（2 +）、镁（2 +）和锌（2 +）的异常调节，这不一定会导致心脏功能障碍。有趣的是，与无多动特质的对应品系相比，多动特质品系中的铜含量升高。然后我们分析了含铜蛋白的mRNA形式的基因表达，最显著的是线粒体 - Cox、Dbh、Lox、Loxl1、Loxl2、Sod1和Tyr。发现Lox、Loxl1、Loxl2和Sod1的基因表达谱在WKHA中特别高，如果这反映了蛋白质含量，那么可以解释WKHA中高铜含量的原因。还检测了其他基因的mRNA，特别是Mb、Fxyd1、Maoa和Maob。我们发现与其他品系相比，SHR中的Maoa基因表达和单胺氧化酶 - A（MAO - A）蛋白含量较低。SHR中MAO - A蛋白含量低而WKHT和WKHA品系中正常这一发现，与MAO - A可预防LVH中心脏功能障碍的发展但不能预防这些大鼠的LVH这一观点最为一致。
