聚西斯-1功能丧失通过DNA损伤反应受损增加了对心房的易感性
bioRxiv : the preprint server for biology
|July 19, 2024
概括
聚西斯-1 (PC1) 缺乏症通过损害心房细胞中的DNA修复,增加了心房动 (AF) 的易感性. 恢复PC1功能或抑制DNA损伤途径可能会降低AF风险.
科学领域:
- 心脏病学 心脏病学
- 腎臟病學 (nephrology) 是一種醫學專業.
- 分子生物学分子生物学
背景情况:
- 心房动 (AF) 和慢性病,如自身主导多性病 (ADPKD),越来越普遍.
- 在Polycystin-1 (PC1) 中的突变导致ADPKD,并与心脏并发症有关,包括AF.
- 在心房心肌细胞中PC1的特定作用及其对心律失常的贡献仍然不太清楚.
研究的目的:
- 调查多素-1 (PC1) 在心房动 (AF) 的发展中的作用.
- 阐明PC1缺乏可能导致AF病变的分子机制.
主要方法:
- 使用的小鼠模型 (Pkd1 R3277C和心肌细胞特定的Pkd1删除) 具有编程电刺激和光学映射.
- 采用了体外模型,包括隔离的心房肌细胞,人类iPSC衍生的心房肌细胞 (hiPSC-aCM) 和HL-1细胞.
- 进行了转录学,分子和生物化学分析,以探索潜在的机制.
主要成果:
- 功能丧失的PC1突变显著增加了AF易感性,并促进了心房附属部分的复发性心律失常.
- 在心房心肌细胞中PC1缺乏导致在压力下增加DNA损伤,并增加心律失常的易感性.
- PARP1 抑制剂和尼古丁胺 рибоoside 降低了PC1 缺乏细胞中的心律失常,这表明DNA 修复通路的作用.
- 人类心房组织中成熟PC1水平的降低表明ADPKD以外的更广泛的相关性.
结论:
- 损坏的PC1增加了AF诱导性,并在体内和体外模型中促进心律失常.
- PC1对DNA损伤起着保护作用,从而降低了AF的易受性.
- 向DNA损伤途径可能为PC1缺陷条件下AF提供治疗策略.
相关概念视频
DNA Damage can Stall the Cell Cycle
9.1K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.1K
Abnormal Proliferation
4.5K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.5K
Cytoskeletal Linker Proteins - Plakins
2.3K
Plakins are large proteins with binding domains for microtubules, microfilaments, intermediate filaments, and membrane-associated protein complexes at cell junctions. Plakin functions are evolutionarily conserved and are primarily involved in organizing the different components of the cytoskeleton by crosslinking them to each other and connecting them to the cell-matrix and cell adhesion complexes. They are also known to interact with signal transducers, serve as scaffolds for signaling...
2.3K
Cystic Fibrosis: Pathogenesis
202
Cystic fibrosis (CF), an autosomal recessive disorder, significantly affects the function of exocrine glands. This genetically inherited disease is characterized by the production of thick and sticky mucus, which can severely affect various organs and systems in the body.
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
202
Long-patch Base Excision Repair
7.0K
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
7.0K
Nucleotide Excision Repair
3.5K
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
3.5K


