PRKAA2

Researchers have made a significant finding in determining the genetic background of dilated cardiomyopathy in Dobermanns. This research helps us understand the genetic risk factors related to fatal diseases of the heart muscle and the mechanisms underlying the disease, and offers new tools for their prevention. Researchers have made a significant finding in determining the genetic background of dilated cardiomyopathy in Dobermanns. This research helps us understand the genetic risk factors related to fatal diseases of the heart muscle and the mechanisms underlying the disease, and offers new tools for their prevention. Researchers from the University of Helsinki and the Folkhälsan Research Center, together with their international partners, have identified the genetic background of dilated cardiomyopathy, a disease that enlarges the heart muscle, in dogs and humans. Based on a dataset encompassing more than 500 Dobermanns, the disease was associated with two nearby genomic loci, where changes were identified in genes that affect the functioning, energy metabolism and structure of the heart muscle. The study revealed that these same risk genes cause heart muscle disease in human patients. A variety of factors can cause cardiomyopathy, but genetics play a significant role. Although dozens of genes underlying cardiomyopathy in humans have been identified, the hereditary nature and genetic background of the disease in dogs have remained unclear. "The situation with Dobermanns is serious in terms of both their health and breeding. The disease has been studied from various angles for decades without significant gene discoveries. Better diagnostic tools are needed, particularly in early diagnostics. Our new research might improve the situation," says Professor Hannes Lohi, the principal investigator in the project. The study has significant implications for veterinary medicine, providing a basis for developing a new genetic test for early diagnostics and breeding. Two novel risk genes identified in an extensive European cohort Various research data collected over decades on more than 500 Dobermanns from across Europe were combined for the research. The dogs in the study cohort were categorised into five different groups: With the help of genetic mapping, two adjacent gene loci in chromosome 5 were associated with dilated cardiomyopathy. Among the numerous genes in the loci, two, namely RNF207 and PRKAA2, demonstrated structural variation, which could have a detrimental effect on the functioning of the genes and cause heart failure. "The genetic mapping we conducted produced important observations. Until now, it has been unclear whether Dobermanns with differing symptoms have the same disease. The genes we identified are only associated with a dilated heart and affected cardiac function. Arrhythmia appears to be a genetically distinct disease. Our dataset was insufficient to identify genes causing arrhythmia only. We also observed that several genes affect cardiac function and identified a model of two genes that increase the disease risk," explains Professor Lohi. Gene discovery in dogs associated with cardiac muscle disorders in humans The significance of the gene discovery in dogs was investigated in human patients diagnosed with dilated cardiomyopathy using Dutch, English (UK Biobank) and Finnish (FinnGen) cohorts. Fifteen potentially harmful and predisposing variants in the same RNF207 and PRKAA2 genes, which had been identified in dogs, were discovered in humans. "The identical genetic background suggests that, to a degree, similar problems with the functioning of the heart muscle lead to dilated cardiomyopathy in both humans and dogs. A deeper understanding of the pathogenetic mechanisms is important, and Dobermanns represent a natural model organism for further research," Lohi states. A genetic test for breeding The DNA markers associated with the disease found in the study may be a step toward a genetic test, but it is important to confirm its clinical significance before such tests are offered. "We discovered how the variants of the two genes together increase the disease risk. However, a pilot is needed to combine genetic and health data to monitor how frequently individuals who belong to the at-risk group develop the disease for varying genetic reasons. Then, we can obtain a more accurate estimate of how the gene discoveries should be ideally interpreted and utilised. In any case, this is a hope-inspiring finding because, in the past, we lacked such tools," Lohi describes. The new gene discoveries enable new research hypotheses For the consistent synchronised pumping of the heart, the heart muscle cells must interact with each other. Unlike in skeletal muscles, in the cell membrane of the heart muscle are finger-like discs that conduct the undulation required for pumping. "Our study revealed that the RNF207 gene is expressed exactly in these discs. Earlier research has shown that RNF207 plays an important role in heart muscle contraction. The absence of these discs has also earlier been linked with cardiomyopathy. The other gene identified, PKAA2, serves as an energy sensor in the heart muscle, and its malfunction can reduce cardiac efficiency. Further research is required to understand the pathogenic mechanism, but we are in a good position to continue. A while ago, the disease was a total mystery, but now we have opened a view to its cellular-level secrets," Professor Lohi concludes. The research was funded by, among others, the Finnish Foundation for Cardiovascular Research, the Jane and Aatos Erkko Foundation, the Sigrid Jusélius Foundation, and many other funders from different countries. The study is part of Professor Hannes Lohi's canine gene research project, and the related article was published in the journal Genome Medicine.

心肌梗死(MI)是一种发病率高、死亡率高的心血管疾病。大多数心肌梗死都是以冠状动脉疾病为基础，合并血液供应急剧减少或中断，使相应的心肌严重而持续的缺血，导致心肌坏死。 心肌梗死(MI)是一种发病率高、死亡率高的心血管疾病。大多数心肌梗死都是以冠状动脉疾病为基础，合并血液供应急剧减少或中断，使相应的心肌严重而持续的缺血，导致心肌坏死。成人心肌组织的坏死往往是不可逆转的，临床上大面积心肌梗死后恢复治疗的预后往往较差。因此，了解心肌保护的机制对于开发合理的药物治疗和改善患者预后是至关重要的。 图片来源: https://doi.org/10.1016/j.omtn.2022.07.009 近日，来自中南大学的研究者们在Molecular Therapy: Nucleic Acids杂志上发表了题为“Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice”的文章，该研究证实了HSF1在二甲双胍治疗小鼠心肌梗死中发挥了更重要的作用。本研究为探讨二甲双胍的药理作用机制和开发新的药物靶点提供了新的思路。 心肌梗死(MI)是一种发病率和死亡率都很高的心血管疾病。临床上，大面积心肌梗死后的康复往往预后较差。因此，有必要探索心肌梗死后心肌保护的治疗方法。二甲双胍作为治疗2型糖尿病的一线药物，已被发现对心肌组织有一定的保护作用。然而，其药理机制尚不清楚。 在这项研究中，研究者研究了二甲双胍降低MI的关键因素。通过体内、体外和电子计算机分析，研究者确定HSF1是二甲双胍的关键靶点。HSF1可通过转录激活上调AMPKa2的转录水平，并刺激下游AMPK/mTOR信号通路的活性。 二甲双胍刺激心肌细胞形成应激颗粒(SGS)，而HSF1基因敲除逆转了这一过程。此外，HSF1对二甲双胍的体外亲和力高于AMPK，提示HSF1可能是二甲双胍更敏感的靶点。 二甲双胍(通过HSF1和AMPK)保护小鼠心肌的作用机制图 图片来源: https://doi.org/10.1016/j.omtn.2022.07.009 在目前的研究中，研究者发现HSF1是二甲双胍缓解小鼠心肌梗死的关键靶点。研究发现，用二甲双胍治疗HSF1基因敲除小鼠的心肌损伤进展更快。此外，HSF1还可激活AMPKa2转录及其下游信号通路。 此外，敲除HSF1可阻断二甲双胍刺激心肌细胞形成应激颗粒(SGS)。在HSF1与AMPK的比较中，二甲双胍与HSF1的亲和力强于AMPK。因此，HSF1在二甲双胍治疗小鼠心肌梗死中发挥了更重要的作用。本研究为探讨二甲双胍的药理作用机制和开发新的药物靶点提供了新的思路。（生物谷 Bioon.com） 参考文献 Mingyuan Wang et al. Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice. Mol Ther Nucleic Acids. 2022 Jul 11;29:312-328. doi: 10.1016/j.omtn.2022.07.009.

糖尿病心肌病(DCM)最初被定义为一种病理生理学疾病，其特征是在没有冠状动脉疾病、高血压或瓣膜心脏病的情况下表现为心力衰竭。结构和功能异常，如左心室肥厚和心肌纤维化，见于DCM的早期阶段，随后是舒张期功能障碍。 如果治疗不当，心脏纤维化和肥大可能会导致心力衰竭，甚至可能死亡。尽管在过去的几十年里，扩张型心肌病的发病机制已经取得了实质性的进展，但针对扩张型心肌病的病理方面的有效干预仍然是必要的。 氢气是一种新型医用气体，具有抗氧化、抗炎、抗凋亡、抗过敏、促进能量代谢等特性。氢气疗法已被证明在治疗心肌缺血、心肌梗死和缺血-再灌注损伤方面有效。氢在扩张型心肌病发病机制中的作用尚不清楚。二甲双胍是一种著名的治疗糖尿病的药理学药物；然而，大剂量药物的应用因其副作用而受到限制。因此，这凸显了开发针对扩张型心肌病的新疗法的重要性。 图片来源: https://doi.org/10.1016/j.freeradbiomed.2022.03.010 近日，哈尔滨医科大学附属第四医院的研究者们在Free Radical Biology and Medicine杂志上发表了题为“Co-administration of hydrogen and metformin exerts cardioprotective effects by inhibiting pyroptosis and fibrosis in diabetic cardiomyopathy”的文章，该研究表明，氢气吸入可通过减少焦亡和纤维化来减轻扩张型心肌病，氢气与二甲双胍联合治疗扩张型心肌病可显示更有效的心脏保护作用。 在本研究中，研究者发现氢改善了链脲佐菌素诱导的糖尿病小鼠的心功能障碍和异常形态结构。作为一种机制，氢气通过抑制AMPK/mTOR/NLRP3信号通路，抑制AMPK/mTOR/NLRP3信号通路，从而抑制其作用；通过抑制转化生长因子-β-1/Smad信号通路，减轻纤维化。 此外，研究者还发现与单独应用二甲双胍相比，氢气和二甲双胍联合应用显示出强大的保护作用，如提高存活率、降低空腹血糖和减少细胞损伤。 氢气和二甲双胍联合应用如何在扩张型心肌病中发挥心脏保护作用的机制图 图片来源: https://doi.org/10.1016/j.freeradbiomed.2022.03.010 综上所述，该研究结果首次揭示了氢在扩张型心肌病中具有心脏保护作用。氢通过抑制AMPK/mTOR/NLRP3途径和通过抑制转化生长因子-β-1/Smad途径发挥抗肝纤维化作用。同时，氢可以与二甲双胍结合，在扩张型心肌病中显示出更有效的心脏保护作用。因此，研究者首次提出二甲双胍和氢气联合用药治疗扩张型心肌炎。 参考文献 Rentong Zou et al. Co-administration of hydrogen and metformin exerts cardioprotective  effects by inhibiting pyroptosis and fibrosis in diabetic cardiomyopathy. Free Radic Biol Med. 2022 Mar 15;183:35-50. doi: 10.1016/j.freeradbiomed.2022.03.010. 内容来源于网络，如有侵权，请联系删除，谢谢