LINC00968 attenuates heart failure by acting as a ceRNA to regulate the miR-22-5p/OPA1 axis

Background Long non-coding RNAs (lncRNAs) regulate heart failure (HF) pathogenesis. This study aimed to investigate the protective role of LINC00968 in HF. Methods 110 HF patients and age-matched healthy controls were recruited for reverse transcription quantitative PCR (RT-qPCR) of LINC00968, miR-22-5p, and OPA1 in serum and peripheral blood mononuclear cells (PBMCs). In vitro, AC16 cardiomyocytes were subjected to angiotensin II (Ang II)-induced injury, followed by flow cytometric analysis of apoptosis and RT-qPCR/ enzyme-linked immunosorbent assay (ELISA) quantification of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), collagen type I, and laminin levels. In vivo, HF was induced in mice via transverse aortic constriction (TAC). The competing endogenous RNA (ceRNA)-mediated interplay among LINC00968, miR-22-5p, and optic atrophy 1 (OPA1) was mechanistically dissected through subcellular fractionation, RNA immunoprecipitation (RIP), and dual-luciferase assays. Results LINC00968 levels were markedly reduced in HF patients, yielding an area under the curve (AUC) of 0.8976 for diagnostic performance. LINC00968 correlated positively with left ventricular ejection fraction (LVEF) and negatively with left ventricular end-diastolic diameter (LVEDD), resting heart rate (HR), and N-terminal pro-B-type natriuretic peptide (NT-proBNP), acting as an independent HF protective factor. In vitro, enforced LINC00968 expression in Ang II-challenged AC16 cardiomyocytes significantly mitigated apoptosis and attenuated the induction of ANP, BNP, collagen type I, and laminin. In TAC mice, cardiac LINC00968 overexpression relieved heart dysfunction. Cytoplasmic LINC00968 sponged miR-22-5p as a ceRNA to de-repress mitochondrial fusion protein OPA1. Rescue experiments confirmed that miR-22-5p mimic reversed LINC00968-mediated OPA1 elevation and cardioprotection, which was recovered by OPA1 overexpression. LINC00968 restored Ang II-suppressed adenosine triphosphate (ATP) production and complex I/IV activities; this benefit was abolished by miR-22-5p mimic and partially rescued via OPA1 overexpression, indicating LINC00968 improves myocardial energy metabolism through the miR-22-5p/OPA1 axis. Conclusion LINC00968 sponged miR-22-5p as a ceRNA to de-repress OPA1, restoring mitochondrial respiration and cardiac function. Clinical trial registration Not applicable.