Kendi, A. | Search bioRxiv

bioRxiv2026

Bioinformatic Characterization of Regulated IRE1a-Dependent Decay (RIDD) in Heart Failure

Inositol-requiring enzyme 1a (IRE1a) is a canonical signaling factor in the unfolded protein response (UPR). In addition to this essential role (which prevents the accumulation of misfolded proteins in the endoplasmic reticulum), the endoribonuclease activity of IRE1a targets multiple mRNAs for degradation through a process called Regulated IRE1a-Dependent Decay (RIDD). The products of over 50 genes have been identified as RIDD targets; however, the biological significance of this process remains underexplored. Using publicly available datasets, we examined the fate of 27 well-characterized RIDD targets in the septal wall of heart failure patients, and in mice subject to pressure overload-induced heart failure. We show that decreased mRNA abundance from these RIDD substrate genes - an outcome consistent with RIDD induction - is commonly observed in heart failure.

cell biology↗

bioRxiv2026

CASC15 dictates vascular smooth muscle cell growth fate and pathological vascular remodeling through post-transcription regulation of mitotic fidelity

Vascular smooth muscle cell (SMC) growth, whether hyperplastic or hypertrophic, is a central determinant of vascular remodeling in cardiovascular disease, yet the molecular regulators that direct SMC toward a specific growth fate remain poorly understood. Here, we identify the long non-coding RNA CASC15 as a critical regulator of SMC growth and vascular remodeling. CASC15 is enriched in the vasculature and SMC-rich tissues in humans and mice, and its locus harbors SNPs significantly associated with coronary artery disease and blood pressure. We identify a novel SMC-selective CASC15 isoform (S-CASC15) whose expression level determines SMC growth fate: elevated S-CASC15 promotes proliferation, while its loss drives hypertrophy, polyploidization, and binucleation. In vivo depletion of CASC15 limits vascular injury-induced neointima formation and atherosclerotic lesion expansion. Conversely, CASC15 overexpression exacerbates injury-induced neointimal hyperplasia. However, CASC15 KO mice exhibit spontaneous medial hypertrophy and vascular hypercontractility. Mechanistically, loss of S-CASC15 expression causes mitotic defects, followed by arrest in the G1 phase of hypertrophic and polyploid cells. We found that S-CASC15 pro-proliferative function is mediated through its interaction with RNA-binding proteins, including Nucleolin, and by regulating the stability of cell cycle checkpoint gene transcripts, thereby ensuring mitotic fidelity. Together, these findings establish CASC15 as a pivotal molecular switch governing the balance between hyperplastic and hypertrophic vascular remodeling and as a potential therapeutic target in cardiovascular disease.

Cell Biology↗