Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease(OHD),which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism.SIRT3,a mitochondria-localized sirtuin,regulates global mitochondrial lysine acetylation and preserves mitochondrial function.However,the mechanisms by which SIRT3 regulates cardiac hypertrophy remains to be further elucidated.In this study,we firstly demonstrated that expression of SIRT3 was decreased in AngiotensionⅡ(AngⅡ)-treated cardiomyocytes and in hearts of AngⅡ-induced cardiac hypertrophic mice.In addition,SIRT3 overexpression protected myocytes from hypertrophy,whereas SIRT3 silencing exacerbated Ang II-induced cardiomyocyte hypertrophy.In particular,SIRT3-KO mice exhibited significant cardiac hypertrophy.Mechanistically,we identified NMNAT3(nicotinamide mononucleotide adenylyltransferase 3),the rate-limiting enzyme for mitochondrial NAD biosynthesis,as a new target and binding partner of SIRT3.Specifically,SIRT3 physically interacts with and deacety.lates NMNAT3,thereby enhancing the enzyme activity of NMNAT3 and contributing to SIRT3-mediated anti-hypertrophic effects.Moreover,NMNAT3 regulates the activity of SIRT3 via synthesis of mitochon.dria NAD.Taken together,these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy.Sirtuin 3(SIRT3),a mitochondrial deacetylase that may play an impor.tant role in regulating cardiac function and a potential target for
Zhong-bao YUEJia YOUZhuo-ming LIShao-rui CHENPei-qing LIU
1型细胞周期蛋白依赖性激酶(cyclin-dependent kinase 1,CDK1)在人体内是有效的抗癌作用靶标.使用三维定量构效关系研究方法,包括比较分子场分析法(comparative molecular field analysis,CoM-FA)和比较分子相似性指数分析法(comparative molecular similarity indices analysis,CoMSIA),分析23个CDK1激酶抑制剂的分子结构与生物活性之间的定量关系.相对其他类型电荷,当训练集加载Gasteiger-Huckel电荷时,CoMFA获得一个最优的三维定量构效关系模型,其交叉验证系数q2为0.668,非交叉验证相关系数R2为0.941,表明模型具有较好的预测能力.使用测试集交叉验证说明该模型稳定可靠,模型中立体场贡献率为69.8%,静电场贡献率为30.2%.
