The effect of aging and pressure overload on the heart of SERCA2a mutant mice

衰老和压力超负荷对SERCA2a突变小鼠心脏的影响

• 批准号: 18590782
• 负责人: MINAMISAWA Susumu
• 金额: $ 1.58万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590782/
• 关键词: cardiology; heypertension; gene; stress; heart failure; calcium

Ca^<2+> cycling via the sarcoplasmic reticulum (SR), an extensive intracellular membrane system of Ca^<2+> store, plays a critical role in maintaining normal cardiac function as well as in development of heart diseases. Cardiac SR Ca^<2+> ATPase (SERCA2a) primarily regulates the rate of Ca^<2+> re-uptake from the cytosole to the SR lumen during relaxation in the heart. A considerable number of studies have demonstrated that the decrease in SERCA2a activity is a common feature of heart failure and that restoring SERCA2a activity prevents the development of heart failure. Phospholamban is a main endogenous inhibitor that suppresses the activity of SERCA2a. Recent studies including ours have demonstrated that mutations in the phospholamban gene are associated with human cardiomyopathy. We found a heterozygous single nucleotide transitions of the SERCA2 gene in one patients with hypertrophic cardiomyopathy. Then, we generated transgenic mice harboring V540A mutant. In addition to phospholamban, a newly identified SR protein, sarcalumenin also regulate Ca^<2+> re-uptake through the interaction with SERCA2a. Sarcalumenin is a Ca^<2+> binding glycoprotein located in the lumen of the SR and thought to regulate Ca^<2+> transport and storage in the SR. Both SERCA2a mutant TG and sarcalumenin knockout mice exhibit mild relaxation-dominant cardiac dysfunction. Here we examined the effect of aging and pressure overload stresses on these mice. These stresses promoted cardiac dysfunction in sarcalumenin KO mice, and then indicated the important role of sarcalumenin-SERCA2a interaction in maintaining cardiac function.

Ca^<2+>通过肌浆网（SR）循环，这是一个广泛的Ca^<2+>储存的细胞膜系统，在维持正常心功能以及心脏病的发生中起着关键作用。心脏SR Ca^<2+> atp酶（SERCA2a）主要调节心脏舒张期间Ca^<2+>从胞底再摄取到SR管腔的速率。相当多的研究表明，SERCA2a活性降低是心力衰竭的共同特征，恢复SERCA2a活性可防止心力衰竭的发展。磷蛋白是抑制SERCA2a活性的主要内源性抑制剂。最近的研究包括我们的研究已经证明，磷蛋白基因的突变与人类心肌病有关。我们在一例肥厚性心肌病患者中发现了SERCA2基因的杂合单核苷酸转移。然后，我们产生了携带V540A突变体的转基因小鼠。除了磷蛋白（一种新发现的SR蛋白）外，sarcalumenin还通过与SERCA2a的相互作用调节Ca^<2+>的再摄取。Sarcalumenin是一种Ca^<2+>结合糖蛋白，位于SR的管腔中，被认为调节Ca^<2+>在SR中的运输和储存。SERCA2a突变体TG和Sarcalumenin敲除小鼠均表现出轻度舒张性优势型心功能障碍。在这里，我们研究了衰老和压力过载对这些小鼠的影响。这些应激促进了sarcalumenin KO小鼠的心功能障碍，从而表明sarcalumenin- serca2a相互作用在维持心功能中的重要作用。

项目成果

Interleukin-15 inhibits smooth muscle cell proliferation and hyaluronan production in rat ductus arteriosus

• DOI: 10.1203/pdr.0b013e31813c9339
• 发表时间: 2007-10-01
• 期刊: PEDIATRIC RESEARCH
• 影响因子: 3.6
• 作者: Iwasaki, Shiho;Minamisawa, Susumu;Yokota, Shumpei
• 通讯作者: Yokota, Shumpei

cAMP-dependent neointimal cushion formation in rat ductus arteriosus

大鼠动脉导管中 cAMP 依赖性新内膜垫形成

• 发表时间: 2007
• 作者: Minamisawa S;et. al.
• 通讯作者: et. al.

cAMP-dependent Intimal Cushion Formation Of the Rat Duct us Arteriosus: The Role Of Epac.

大鼠动脉导管的 cAMP 依赖性内膜垫形成：Epac 的作用。

• 发表时间: 2007
• 作者: Quan H;et. al.
• 通讯作者: et. al.

Multiple transcripts of Ca^<2+> channel subunits and a novel spliced variant of al C subunit in the rat ductus arteriosus

大鼠动脉导管中Ca^2通道亚基的多个转录物和al C亚基的新剪接变体

• 发表时间: 2006
• 期刊: Am J Physiol Heart Circ Physiol 290(4)
• 作者: Yokoyama;U.;Minamisawa;S.;Adachi-Akahane;S.,Akaike;T.;Naguro;I.;Funakoshi;K.;Iwamoto;M.;Nakagone;M.;Uemura;N.;Hori;H.;Yokota;S.;Ishikawa;Y
• 通讯作者: Y

Mechanical Stress-dependent transcriptional regulagion of the sarcolipin gene in the rodent atrium

啮齿动物心房中肌磷脂基因的机械应激依赖性转录调节

• 发表时间: 2005
• 期刊: Biochem Biophys Res Commun 334
• 作者: Shimura M;et. al.
• 通讯作者: et. al.