Department of Medicine, Division of Cardiovascular Disease, The University of Alabama at Birmingham 703 19th St. South, ZRB-302, Birmingham, AL 35233, USA.
Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, USA.
Cardiovasc Res. 2022 Jun 22;118(7):1680-1692. doi: 10.1093/cvr/cvab160.
Among several known RNA modifications, N6-methyladenosine (m6A) is the most studied RNA epitranscriptomic modification and controls multiple cellular functions during development, differentiation, and disease. Current research advancements have made it possible to examine the regulatory mechanisms associated with RNA methylation and reveal its functional consequences in the pathobiology of many diseases, including heart failure. m6A methylation has been described both on coding (mRNA) and non-coding RNA species including rRNA, tRNA, small nuclear RNA and circular RNAs. The protein components which catalyze the m6A methylation are termed methyltransferase or 'm6A writers'. The family of proteins that recognize this methylation are termed 'm6A readers' and finally the enzymes involved in the removal of a methyl group from RNA are known as demethylases or 'm6A erasers'. At the cellular level, different components of methylation machinery are tightly regulated by many factors to maintain the m6A methylation dynamics. The m6A methylation process impacts different stages of mRNA metabolism and the biogenesis of long non-coding RNA and miRNA. Although, mRNA methylation was initially described in the 1970s, its regulatory roles in various diseases, including cardiovascular diseases are broadly unexplored. Recent investigations suggest the important role of m6A mRNA methylation in both hypertrophic and ischaemic heart diseases. In the present review, we evaluate the significance of m6A methylation in the cardiovascular system, in cardiac homeostasis and disease, all of which may help to improve therapeutic intervention for the treatment of heart failure. RNA methylation in cardiovascular diseases: altered m6A RNA (coding and non-coding RNA) methylation is identified during different cardiovascular diseases. Increased cardiac hypertrophy is observed following METTL3 overexpression. In contrast, reduced FTO level was seen in mice following myocardial infarction. Increased cardiac fibroblasts activation or increased atherosclerotic plaques were also co-related with m6A RNA methylation.
在几种已知的 RNA 修饰中，N6-甲基腺苷（m6A）是研究最多的 RNA 转录后修饰物，它在发育、分化和疾病过程中控制多种细胞功能。目前的研究进展使得研究与 RNA 甲基化相关的调控机制并揭示其在许多疾病（包括心力衰竭）的病理生物学中的功能后果成为可能。m6A 甲基化已被描述为编码（mRNA）和非编码 RNA 物种，包括 rRNA、tRNA、小核 RNA 和环状 RNA。催化 m6A 甲基化的蛋白质成分被称为甲基转移酶或“m6A 写入器”。识别这种甲基化的蛋白质家族被称为“m6A 读取器”，最后，从 RNA 上去除甲基基团的酶被称为去甲基酶或“m6A 橡皮擦”。在细胞水平上，甲基化机制的不同成分受到许多因素的严格调节，以维持 m6A 甲基化动力学。m6A 甲基化过程影响 mRNA 代谢和长非编码 RNA 和 miRNA 生物发生的不同阶段。尽管 m6A 甲基化最初是在 20 世纪 70 年代描述的，但它在包括心血管疾病在内的各种疾病中的调节作用尚未得到广泛探索。最近的研究表明，m6A mRNA 甲基化在肥厚性和缺血性心脏病中都具有重要作用。在本综述中，我们评估了 m6A 甲基化在心血管系统、心脏稳态和疾病中的重要性，这可能有助于改善心力衰竭治疗的治疗干预。心血管疾病中的 RNA 甲基化：在不同的心血管疾病中，发现 m6A RNA（编码和非编码 RNA）甲基化发生改变。METTL3 过表达后观察到心脏肥大增加。相反，心肌梗死后小鼠的 FTO 水平降低。心脏成纤维细胞激活增加或动脉粥样硬化斑块增加也与 m6A RNA 甲基化相关。
