Pulmonary Hypertension: Molecular Mechanisms and Clinical Studies

Abstract

Pulmonary hypertension (PH) stands as a tumor paradigm cardiovascular disease marked by hyperproliferation of cells and vascular remodeling, culminating in heart failure. Complex genetic and epigenetic mechanisms collectively contribute to the disruption of pulmonary vascular homeostasis. In recent years, advancements in research technology have identified numerous gene deletions and mutations, in addition to bone morphogenetic protein receptor type 2, that are closely associated with the vascular remodeling process in PH. Additionally, epigenetic modifications such as RNA methylation, DNA methylation, histone modification, and noncoding RNAs have been shown to precisely regulate PH molecular networks in a cell-type-specific manner, emerging as potential biomarkers and therapeutic targets. This review summarizes and analyzes the roles and molecular mechanisms of currently identified genes and epigenetic factors in PH, emphasizing the pivotal role of long ncRNAs in its regulation. Additionally, it examines current clinical and preclinical therapies for PH targeting these genes and epigenetic factors and explores potential new treatment strategies.

Keywords: clinical therapeutics; epigenetic; genetic; noncoding RNAs; pulmonary hypertension.

FIGURE 1

WHO group classification and the pathologic characteristics of PH. PAH, pulmonary arterial hypertension; PAECs, pulmonary artery endothelial cells; PASMCs, pulmonary artery smooth muscle cells; PAFs, pulmonary arterial fibroblasts; HIV, human immunodeficiency virus; CMs, cardiomyocytes; CFs, cardiac fibroblasts.

FIGURE 2

The role of BMPR2 and CAV‐1 in PAH. (A) The role of BMPR2 in PH. In PAECs and PASMCs, mutations in BMPR2 lead to a reduction in BMPR2 protein levels, disrupting the BMP signaling pathway and promoting excessive cell proliferation. Additionally, in PAECs, BMPR2 mutations contribute to PH by inhibiting IL‐15Ra expression at the cell membrane through disruption of the trans‐Golgi network. Furthermore, in PASMCs, reduced BMPR2 levels affect histone methylation, leading to increased NFYA expression, which in turn enhances cell cycle progression and glycolytic protein expression, further driving pathological remodeling in PH. (B) The role of CAV‐1 in PH. Similarly, a decrease in Cav‐1 at the cell membrane in both PAECs and PASMCs contributes to the development of PH. In PAECs, the oxidant molecule peroxynitrite, produced by NOX1 and iNOS, modifies Cav‐1, leading to reduced calcium influx in vascular endothelial cells. This inhibits vasodilation and promotes PH. Additionally, Cavin‐1 competitively binds to Cav‐1, reducing BMPR2 levels at the cell membrane, thereby inhibiting its downstream signaling and driving vascular remodeling. Vascular injury‐induced shedding of MVs and sAB depletes Cav‐1, further decreasing BMPR2 levels. This shedding also enhances TGF‐β production by macrophages, contributing to disease progression. In PASMCs, activation of PPARγ by the agonist GW1929 requires Cav‐1 and leads to increased p38 and ERK1/2 phosphorylation, promoting apoptosis while inhibiting proliferation. Moreover, PPARγ activation by GW1929 significantly reduces hypoxia‐induced Cav‐1 upregulation, establishing a negative feedback mechanism that regulates its expression. PAEC, pulmonary artery endothelial cell; PASMC, pulmonary artery smooth muscle cell; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PAEC, pulmonary artery endothelial cell; PASMC, pulmonary artery smooth muscle cell; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; GW1929, a PPARγ agonist; MVs, microvesicles; sAB, small apoptotic bodies; CSD, caveolin scaffolding domain; NK, cell natural killer cell.

FIGURE 3

The role of RNA methylation, DNA methylation, and demethylation in PH. (A) RNA methylation primarily affects RNA stability and gene expression. In PASMCs, hypoxia‐induced reduction of METTL3 inhibits m6A methylation, leading to cellular phenotypic shifts and pyroptosis. Additionally, hypoxia increases Alkbh5, which promotes cell migration and proliferation by destabilizing Cyp1a1 mRNA, contributing to PH. However, some studies also suggest that hypoxia‐induced upregulation of METTL3 can drive phenotypic changes. In MCT‐induced PH, elevated YTHDF1 enhances the translation of MAGED1 and FoxM1, accelerating disease progression, while YTHDF2 upregulation in PASMCs promotes proliferation via the m6A/Myadm/p21 pathway. In PAECs, TNF‐α and TGF‐β1 suppress METTL3, reducing RNA methylation and leading to vascular remodeling and phenotypic changes. Furthermore, hypoxia‐induced inhibition of FENDRR by YTHDC1 decreases DRP1 promoter methylation, promoting DRP1 expression and contributing to PH development. (B) DNA methylation and demethylation regulate key gene expression, influencing cell proliferation, phenotypic switching, and vascular remodeling. In PASMCs, methylation of the SOD2 gene suppresses its expression, leading to HIF‐1 activation and phenotypic changes, while methylation of the ELK3 gene induces mitochondrial dysfunction, further promoting cellular shifts that contribute to PH. In PAECs, hypermethylation of the BMPR2 promoter and the CTSZ gene impairs BMPR2 activity and apoptosis, facilitating vascular remodeling and disease progression. Additionally, in male PAECs, EHITSN upregulates Xist expression, altering the methylation of the Xist/Tsix locus, which reduces KLF2 expression and drives vascular remodeling, ultimately leading to PH. PASMC, pulmonary artery smooth muscle cell; PAEC, pulmonary artery endothelial cell; m6A, N6‐methyladenosine; pri‐miR, primary microRNA; PH, pulmonary hypertension; PM, particulate matter.

FIGURE 4

The role of lncRNAs in PH. The literature has established that 27 lncRNAs either promote or inhibit the pathogenesis of PH by interacting with miRNAs or protein molecules. PASMC, pulmonary artery smooth muscle cell; PAEC, pulmonary artery endothelial cell; EndMT, endothelial‐to‐mesenchymal transition; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension.

FIGURE 5

The therapeutic strategies targeting lncRNAs in PH. In PH, specific lncRNAs are upregulated or downregulated, causing lncRNA imbalance and dysregulation of related genes and proteins. Targeting approaches involve regulating associated genes/proteins and balancing lncRNA expression using antisense oligonucleotides, RNA modification/interference, CRISPR, and protein therapy. Emerging transplantation strategies such as stem cell and mitochondrial transplantation (intravenous or oral) are highlighted as potential interventions for restoring cellular homeostasis. PH, pulmonary hypertension; lncRNA, long noncoding RNA; CRISPR, clustered regularly interspaced short palindromic repeats.