K.G. Jebsen Center of Exercise in Medicine at the Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
K.G. Jebsen Center of Exercise in Medicine at the Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Prog Cardiovasc Dis. 2019 Mar-Apr;62(2):193-202. doi: 10.1016/j.pcad.2019.03.002. Epub 2019 Mar 10.
The benefits of physical activity in cardiovascular diseases have long been appreciated. However, the molecular mechanisms that trigger and sustain the cardiac benefits of exercise are poorly understood, and it is anticipated that unveiling these mechanisms will identify novel therapeutic targets. In search of these mechanisms we took advantage of unbiased RNA-sequencing (RNA-seq) technology to discover cardiac gene targets whose expression is disrupted in heart failure (HF) and rescued by exercise in a rat model. Upon exhaustive validation in a separate rat cohort (qPCR) and human datasets, we shortlisted 16 targets for a cell-based screening, aiming to evaluate whether targeted disruption of these genes with silencing RNA would affect the abundance of a CVD biomarker (BNP, B-type natriuretic peptide) in human cardiomyocytes. Overall, these experiments showed that Proline Dehydrogenase (PRODH) expression is reduced in human failing hearts, rescued by exercise in a rat model of HF, and its targeted knockdown increases BNP expression in human cardiomyocytes. On the other hand, overexpression of PRODH increases the abundance of metabolism-related gene transcripts, and PRODH appears to be crucial to sustain normal mitochondrial function and maintenance of ATP levels in human cardiomyocytes in a hypoxic environment, as well as for redox homeostasis in both normoxic and hypoxic conditions. Altogether our findings show that PRODH is a novel molecular target of exercise in failing hearts and highlight its role in cardiomyocyte physiology, thereby proposing PRODH as a potential experimental target for gene therapy in HF.
体育活动对心血管疾病的益处早已被人们所认识。然而，运动对心脏有益的触发和维持的分子机制仍知之甚少，可以预见，揭示这些机制将确定新的治疗靶点。为了寻找这些机制，我们利用无偏 RNA 测序（RNA-seq）技术发现了在心力衰竭（HF）中表达失调、并在大鼠模型中通过运动得到挽救的心脏基因靶点。在另一组大鼠（qPCR）和人类数据集进行了详尽的验证后，我们为基于细胞的筛选列出了 16 个靶点，旨在评估用沉默 RNA 靶向这些基因的破坏是否会影响人类心肌细胞中 CVD 生物标志物（BNP，B 型利钠肽）的丰度。总的来说，这些实验表明，脯氨酸脱氢酶（PRODH）在人类衰竭的心脏中表达减少，在 HF 的大鼠模型中通过运动得到挽救，其靶向敲低会增加人类心肌细胞中 BNP 的表达。另一方面，PRODH 的过表达会增加与代谢相关的基因转录本的丰度，并且 PRODH 似乎对维持人类心肌细胞在缺氧环境中的正常线粒体功能和 ATP 水平以及在正常和缺氧条件下的氧化还原平衡至关重要。总之，我们的研究结果表明，PRODH 是心力衰竭中运动的一个新的分子靶点，并强调了它在心肌细胞生理学中的作用，从而提出 PRODH 作为心力衰竭基因治疗的潜在实验靶点。
