Key result
Diminazene aceturate ameliorates hypertensive cognitive impairment by degrading CCN1 mRNA to restore mitochondria.
Why the study?
Molecular mechanisms underlying hypertension-induced neuronal injury remain poorly understood, and the mechanisms of diminazene aceturate in hypertensive brain damage were unknown.
Does diminazene aceturate ameliorate hypertension-induced cognitive impairment in preclinical models?
Does diminazene aceturate ameliorate hypertension-induced cognitive impairment in preclinical models?
Diminazene aceturate confers neuroprotective effects against hypertension-induced cognitive impairment by disrupting the CCN1–integrin αvβ6–TGF-β axis and preserving mitochondrial integrity.
Hypothesis-generating for diminazene aceturate in hypertension-induced cognitive impairment; prospective trials needed before clinical adoption.
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.
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Huo et al. (2026) studied this question. Diminazene aceturate ameliorates hypertension-induced cognitive impairment by accelerating CCN1 mRNA degradation to disrupt integrin αvβ6–TGF-β signaling and restore mitochondrial function.
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