Genetic blockade of the activation of 26S proteasomes by PKA is well tolerated by mice at baseline.

IF 1.3
American journal of cardiovascular disease Pub Date : 2024-04-15 eCollection Date: 2024-01-01 DOI:10.62347/NSWR6869
Liuqing Yang, Md Salim Ahammed, Penglong Wu, Jack O Sternburg, Jinbao Liu, Xuejun Wang
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引用次数: 0

Abstract

Objective: Proteasome activation by the cAMP-dependent protein kinase (PKA) was long suggested and recent studies using both cell cultures and genetically engineered mice have established that direct phosphorylation of RPN6/PSMD11 at Serine14 (pS14-RPN6) mediates the activation of 26S proteasomes by PKA. Genetic mimicry of pS14-RPN6 has been shown to be benign at baseline and capable of protecting against cardiac proteinopathy in mice. Here we report the results from a comprehensive baseline characterization of the Rpn6S14A mice (S14A), the first animal model of genetic blockade of the activation of 26S proteasomes by PKA.

Method: Wild type and homozygous S14A littermate mice were subjected to serial M-mode echocardiography at 1 through 7 months of age, to left ventricular (LV) catheterization via the carotid artery for assessment of LV mechanical performance, and to cardiac gravimetric analyses at 26 weeks of age. Mouse mortality and morbidity were monitored daily for up to one year. Males and females were studied in parallel.

Results: Mice homozygous for S14A were viable and fertile and did not show discernible developmental abnormalities or increased mortality or morbidity compared with their Rpn6 wild type littermates by at least one year of age, the longest cohort observed thus far. Neither serial echocardiography nor hemodynamic assessments detected a remarkable difference in cardiac morphometry and function between S14A and wild type littermate mice. No cardiac gravimetric difference was observed.

Conclusion: The findings of the present study indicate that genetic blockade of the activation of 26S proteasomes by PKA is well tolerated by mice at baseline. Therefore, the S14A mouse provides a desirable genetic tool for further investigating the in vivo pathophysiological and pharmacological significance of pS14-RPN6.

基因阻断 PKA 对 26S 蛋白酶体的激活,小鼠在基线期的耐受性很好。
目的:蛋白酶体由 cAMP 依赖性蛋白激酶(PKA)激活的说法由来已久,最近利用细胞培养物和基因工程小鼠进行的研究证实,RPN6/PSD11 在丝氨酸 14 处的直接磷酸化(pS14-RPN6)介导了 PKA 对 26S 蛋白酶体的激活。pS14-RPN6的基因模拟已被证明在基线上是良性的,并能保护小鼠免受心脏蛋白病的影响。在此,我们报告了 Rpn6S14A 小鼠(S14A)的全面基线特征研究结果,这是首个通过 PKA 激活 26S 蛋白酶体的遗传阻断动物模型:方法:野生型小鼠和同卵S14A小鼠在1至7月龄时接受连续的M型超声心动图检查,经颈动脉进行左心室导管检查以评估左心室的机械性能,并在26周龄时进行心脏重力分析。在长达一年的时间里,每天都对小鼠的死亡率和发病率进行监测。雌雄小鼠同时进行研究:结果:与 Rpn6 野生型同窝小鼠相比,S14A 基因同源小鼠至少在一岁前都能存活并具有生育能力,而且没有出现明显的发育异常,死亡率或发病率也没有增加。序列超声心动图和血液动力学评估均未发现 S14A 与野生型同窝小鼠在心脏形态和功能方面存在显著差异。没有观察到心脏重力差异:本研究结果表明,小鼠对 PKA 激活 26S 蛋白酶体的基因阻断基线耐受性良好。因此,S14A 小鼠为进一步研究 pS14-RPN6 的体内病理生理学和药理学意义提供了一种理想的遗传工具。
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来源期刊
American journal of cardiovascular disease
American journal of cardiovascular disease CARDIAC & CARDIOVASCULAR SYSTEMS-
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