Vitronectin-driven amyloid deposition disrupts mitochondrial homeostasis via integrin-mediated pathway in a humanized mouse model of transthyretin cardiac amyloidosis.

BACKGROUND AND AIMS: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive cause of heart failure, especially in the ageing society, but cellular biological mechanism studies are limited by the lack of robust animal models. Vitronectin (VTN), an extracellular matrix (ECM) glycoprotein enriched in amyloid deposits, may contribute to amyloidogenesis, yet its pathogenic role in ATTR-CM remains undefined. METHODS: Humanized knock-in mice expressing either wild-type (hTTRWT) or V142I mutant transthyretin (hTTRV142I) were generated. Amyloid burden, cardiac structure, and function were assessed by Congo red staining, electron microscopy, echocardiography, and cardiac magnetic resonance. The functional role of VTN and integrin signalling was studied using genetic silencing and pharmacological intervention with low-dose cilengitide. RESULTS: Both hTTRWT and hTTRV142I mice developed age-dependent cardiac amyloidosis with diastolic dysfunction and reduced survival, especially in the hTTRV142I strain. VTN co-localized with TTR fibrils, promoted fibril aggregation, reduced amyloid burden upon its knockdown, and preserved cardiac function. Mechanistically, TTR amyloid suppressed integrin αvβ3/FAK/Akt signalling, leading to marked mitochondrial dysregulation characterized by excessive fission, enhanced mitophagy, and impaired oxidative phosphorylation. Restoration of αvβ3 signalling with cilengitide normalized mitochondrial dynamics, improved bioenergetics, and ameliorated diastolic dysfunction despite persistent amyloid stress. CONCLUSIONS: Two reproducible ATTR-CM models that recapitulate the steadily progressive course of human disease were established. Furthermore, VTN actively drives cardiac amyloid deposition, and disruption of integrin αvβ3/FAK/Akt signalling links amyloid-ECM interactions to mitochondrial dysfunction. Therefore, modulation of integrin signalling represents a potential complementary therapeutic strategy in ATTR-CM beyond TTR suppression.