Calpain inhibition as a novel therapeutic strategy for aortic dissection with acute lower extremity ischemia.

Abstract

Background: Aortic dissection (AD) patients with malperfusion present significant challenges and are associated with high postoperative mortality rates. Limited data exist regarding the management of patients with AD and acute lower extremity ischemia. Early diagnosis of the extent of malperfusion and timely intervention are critical for improving patient prognosis.

Methods: A total of 104 patients diagnosed with AD were enrolled in this observational retrospective study, of which 11 (10.6%) presented with lower limb ischemia (LLI). A comparative analysis was conducted on the clinical data of the AD group and the AD + LLI group. Plasma concentrations of SBDP145, a specific indicator of Calpain activity, were quantified in Control, AD, and AD + LLI groups using ELISA. To explore the role of Calpain in LLI and AD, pharmacological inhibition with Calpeptin and transgenic mice overexpressing calpastatin (Tg-CAST) were utilized in mouse models. RNA sequencing and functional assays were employed to identify the downstream effectors of Calpain.

Results: Patients in the AD + LLI group exhibited significantly elevated leukocyte counts, percentages of neutrophils and lymphocytes, as well as increased serum levels of AST, creatinine, total cholesterol, low-density lipoprotein, uric acid, and creatine kinase compared to those in the AD group. Furthermore, the mean calcium ion concentration and Ca²⁺-dependent Calpain activation were significantly higher in the AD + LLI patients. Both endogenous and exogenous Calpain inhibitors effectively promoted the restoration of blood flow to ischemic hind limbs by inhibiting the inflammatory response and promoting vascular regeneration. Additionally, Calpain inhibition prevented the onset and progression of AD. RNA sequencing and Western Blot assays demonstrated that Calpain inhibition significantly increased levels of Fabp3, which is involved in the ischemia-induced fatty acid metabolism pathway.

Conclusions: Inhibition of Calpain has been demonstrated to decrease the incidence of AD and enhance the restoration of blood flow perfusion in ischemic lower extremities. This effect may be mediated by the upregulation of Fabp3. These findings highlight the potential for targeted interventions against Calpain as a novel therapeutic strategy in the treatment of cardiovascular disease.