Diminazene Aceturate Ameliorates Hypertension-Induced Cognitive Impairment by Disrupting the CCN1-Integrin αvβ6-TGF-β...

Hypertension is a critical risk factor for vascular cognitive impairment; however, the precise molecular mechanisms underlying hypertension-induced neuronal injury remain poorly understood, hindering the development of effective neuroprotective strategies. Diminazene aceturate (DIZE), an activator of angiotensin-converting enzyme 2 (ACE2), has demonstrated neuroprotective effects in various neurological injury models, though its mechanisms in hypertensive brain damage are unknown. Here, we investigate the role of the matricellular protein CCN1 in hypertension-associated cognitive impairment and elucidate the potential neuroprotective mechanisms conferred by DIZE. A total of 80 genes were identified using RNA sequencing of HT22 hippocampal neurons treated with angiotensin II (AngII) alone or AngII plus DIZE, with CCN1 emerging as a hub linking mitochondrial dysfunction, autophagy, and oxidative stress pathways. In vitro, AngII-induced CCN1 upregulation, mitochondrial dysfunction, membrane-potential collapse, and excessive reactive oxygen species production were rescued by DIZE co-treatment. Mechanistically, CCN1 activated integrin αvβ6-TGF-β signaling to mediate neuronal injury, as these detrimental effects induced by AngII were abolished by genetic CCN1 knockdown or pharmacological blockade of integrin αvβ6 or TGF-β receptor 1, confirming a CCN1-αvβ6-TGF-β signaling axis. Actinomycin D transcription inhibition assays demonstrated that DIZE suppressed CCN1 at the post-transcriptional level, specifically by accelerating CCN1 mRNA degradation and reducing its half-life, thereby restoring mitochondrial integrity. Building on these mechanistic insights, chronic hypertension was induced in mice by continuous subcutaneous AngII infusion. AngII-induced spatial-memory and object-recognition deficits in Barnes maze, novel object recognition, and Y-maze tests were largely reversed by DIZE treatment, demonstrating that restoration of mitochondrial function through CCN1 destabilization ameliorates hypertension-related cognitive impairment. We identify a novel CCN1-integrin αvβ6-TGF-β-mitochondrial dysfunction signaling axis as a key mediator of hypertension-induced cognitive impairment and demonstrate that DIZE confers neuroprotective effects through post-transcriptional suppression of CCN1 via accelerated mRNA degradation. These findings advance our mechanistic understanding of hypertensive brain injury and establish a rational foundation for the clinical development of CCN1-targeted therapeutic interventions.