Long Non-coding RNA PEBP1P2 Suppresses Proliferative VSMCs Phenotypic Switching and Proliferation in Atherosclerosis

Abstract

Long non-coding RNAs (lncRNAs) play a crucial role in the growth of vascular smooth muscle cells (VSMCs), the dysfunction of which is closely associated with the initiation and progression of cardiovascular diseases (CVDs). Abnormal phenotypic switching and proliferation of VSMCs constitute a significant event in the progression of atherosclerosis. The present study identified a novel lncRNA, PEBP1P2, which serves as a valuable regulator of VSMCs in phenotypic transformation and proliferation. The expression of PEBP1P2 was remarkably decreased in proliferating VSMCs and pathological arteries when using a balloon injury model of rats. Furthermore, we found that PEBP1P2 represses proliferation, migration, and dedifferentiation during phenotype switching in VSMCs induced by platelet-derived growth factor BB (PDGF-BB). Mechanistically, cyclin-dependent kinase 9 (CDK9) was confirmed to be the direct target of PEBP1P2, which was proven to mediate phenotypic switching and proliferation of VSMCs and was rescued by PEBP1P2. Then, we explored the clinical significance, as we observed the decreased expression of PEBP1P2 in the serum of coronary heart disease (CHD) patients and human advanced carotid atherosclerotic plaques. Finally, PEBP1P2 overexpression distinctly suppressed neointima formation and VSMC phenotypic switching in vivo . Taken together, PEBP1P2 inhibits proliferation and migration in VSMCs by directly binding to CDK9, implying that it may be a promising therapeutic target for the treatment of proliferative vascular diseases.

Role of acetylation in doxorubicin-induced cardiotoxicity

“…It participates in mRNA conditioning networks via competing endogenous RNA (ceRNA)-mediated miRNA evasion. MiR-221-3p is a target ceRNA of NEAT1 and its enrichment in aged myocardial tissues could impair myocardium regeneration by suppressing the sirtuin family [ [107] , [108] , [109] ]. MiR-221-3p interacts with the 3′-UTR of Sirt2 to inhibit Sirt2 expression at the post-transcriptional level, and Sirt2 activates AMPK to attenuate age-related cardiac hypotrophy and DOX-induced cardiotoxicity, implying that the exosome/NEAT1/miR-221-3p/Sirt2 pathway attenuates cardiomyocyte senescence [ 110 , 111 ].…”

The cellular function and molecular mechanism of formaldehyde in cardiovascular disease and heart development

“…In recent years, the roles of non‐coding RNAs (ncRNAs), including microRNAs, long non‐coding (lnc) RNAs and circulating (circ) RNAs, in disease pathogenesis, regulatory mechanisms and therapeutic applications have gradually become hot areas of research 90‐93 . Moreover, ncRNA has been shown to have an important regulatory role in CVD, 92,94‐105 tumours, 106 inflammation, 103,107 and heart development 108,109 . Increasing studies have shown that ncRNAs constitute potentially important players in biological regulation 110 .…”

Targeting the phenotypic switch of vascular smooth muscle cells to tackle atherosclerosis

“…Among them are SMILR and MALAT1 [42]; the mechanism of their action is not fully understood, however, most likely it involves "sponging" or acting as a decoy for miRNAs [43]. Other lncRNAs that have been shown to modulate VSMC biology are CARMN, PEBP1P2, PVT1, NEAT1, AK098656, and ANRIL [2,[44][45][46][47][48].…”