RNA methylation, metabolic reprogramming and pulmonary hypertension

Pulmonary hypertension (PH) is a progressive disease characterized by pulmonary vascular remodeling, sustained elevated pulmonary vascular resistance, and pulmonary arterial pressure, culminating in right heart failure and premature mortality. Decades of research have yielded significant strides in comprehending the molecular mechanisms involved in pulmonary vascular remodeling and PH, enabling the development of targeting drugs and clinical diagnosis optimization. Nevertheless, PH remains a complicated clinical syndrome with non-specific manifestations. Meanwhile, the existing drugs are not universally effective, being able to mitigate only clinical symptoms, but fail to preventing or reversing pathological vascular remodeling progress. Hence, the identification of new diagnostic markers and intervention targets remains paramount to diminish misdiagnosis and advance precision medicine. Epigenetic modifications play a pivotal role in pulmonary vascular remodeling and PH pathogenesis. RNA methylation, a reversible chemical modification of RNA, has recently gained much attention from researchers, demonstrating significant roles in the onset and progression of PH. This encompasses phenotypic switch of smooth muscle cells, dysfunction of endothelial cells, and inflammatory responses of monocytes/macrophages. Gene ablation of RNA methylation modulators in SuHx (SU5416+Hypoxia) mice shows reduced pulmonary vascular remodeling and improved hemodynamic parameters in vivo. Meanwhile, inhibition of RNA methylation modulators also improves the proliferation of vascular cells and activation of macrophages in vitro. In addition, numerous studies have underscored abnormal metabolic reprogramming as a universal hallmark of PH, such as increased glucose uptake, glycolysis, fatty acid oxidation, and glutamate metabolism. All these dysfunctions of metabolic reprogramming in various vascular and perivascular cells can exacerbate pulmonary vascular remodeling. Of note, a large number of studies have shown that inhibition of metabolic reprogramming could also reverse right heart dysfunction and vascular cell proliferation in vivo and in vitro. Thus, targeting the key modulators of RNA methylation and (or) metabolic reprogramming might be an effective method in PH treatment. With the rapid development of sequencing technology and further in-depth research on PH, increasing evidence has indicated that RNA methylation modification and metabolic reprogramming could regulate each other and jointly participate in various diseases. However, it remains unclear whether these processes synergistically promote the progression of PH. To that end, this review systematically introduces the main types and functions related to RNA methylation and metabolic reprogramming, comprehensively organizing recent advances in RNA methylation and metabolic reprogramming in PH pathogenesis. Furthermore, we outline the potential association of RNA methylation and metabolic reprogramming in synergistically regulating PH progression. We believe that a deeper understanding of the metabolic and epigenetic mechanisms underlying PH will furnish crucial insights for designing new therapeutics and advance our knowledge of PH pathogenesis.