Divergent Effects of PKC (Protein Kinase C)a in the Human and Animal Heart? Therapeutic Implications for PKC Inhibitors in Cardiac Patients

Kate L. Weeks; Julie R. McMullen

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Divergent Effects of PKC (Protein Kinase C)a in the Human and Animal Heart? Therapeutic Implications for PKC Inhibitors in Cardiac Patients

机译：发散PKC(蛋白激酶C)的影响人类和动物的心脏吗?影响心脏的PKC抑制剂病人

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The PKC (protein kinase C) family consists of ≈13 members within 3 classes. PKCa belongs to the conventional/classical class of PKCs, together with PKCβ1, PKCβ2, and PKCγ. The conventional PKCs are Ca2+ and lipid activated and function downstream of Gq protein-coupled receptor signaling, which, when over activated, causes pathological cardiac remodeling and heart failure.1 PKCa and PKCβ1/II have been identified in the rodent and human heart, and PKCa expression or activity have been reported to increase in the diseased heart.1 Studies in PKCa genetic mouse models, and preclinical studies with PKC inhibitors in rodents and large animal models, have consistently suggested that inhibiting PKCa in the failing heart would be beneficial.2-9 The PKC inhibitors used have not been specific for PKCa alone (eg, ruboxistaurin, Ro-32-0432, and Ro-31-8220 inhibit PKCa/β/γ). However, PKCa is the most abundant isoform in mouse heart (based on protein content)10 and ruboxistaurin was shown to provide benefit in PKCβ/γ-/-mice subjected to pressure overload, the beneficial effects of these inhibitors has been attributed to inhibition of PKCa.2 The development of PKC-specific inhibitors has been of interest for several diseases, including those of cardiac pathogenesis (heart failure and atherosclerosis). However, to date, results from clinical trials have been disappointing.1

机译：蛋白激酶C (PKC)的家庭由≈13成员在3类。常规/古典类PKCs的在一起与PKCβ1,PKCβ2,PKCγ。PKCs Ca2 +和脂质活性和功能下游的Gq protein-coupled受体信号,当激活,原因病理性心脏重构和心脏failure.1在啮齿动物和人类心脏,PKCa表达式或活动已报告增加患病的heart.1基因小鼠模型,和临床前研究用PKC抑制剂在啮齿动物和大型动物模型,一直暗示抑制PKCa失败的心里有益的。独自被特定PKCa(如ruboxistaurin,Ro-32-0432,和Ro-31-8220 inhibit PKCa -βγ)。然而,PKCa是最丰富的同种型老鼠的心脏(基于蛋白质含量)10ruboxistaurin被证明提供的好处PKCβ/γ- /小鼠受到压力过载这些抑制剂的有利影响归因于PKCa.2抑制PKC-specific抑制剂的发展感兴趣的几个疾病,包括那些心脏发病机理(心脏衰竭和动脉粥样硬化)。临床试验已经disappointing.1

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来源
《Circulation. Genomic and precision medicine.》 |2018年第3期|e002104-e002104|共1页
作者
Kate L. Weeks; Julie R. McMullen;
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作者单位

Department of Cardiac Hypertrophy, Baker Heart and Diabetes Institute, Melbourne, Victoria;

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正文语种英语
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Heart; Heart Failure; cardiac patientruboxistaurinRo 31-8220Mouse HeartAnimal modelsRodentReceptor SignalingHuman;

机译：31-8220Mouse HeartAnimal modelsRodentReceptorSignalingHuman;

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Divergent Effects of PKC (Protein Kinase C)a in the Human and Animal Heart? Therapeutic Implications for PKC Inhibitors in Cardiac Patients

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