Effects of cPIP2 peptide and rosuvastatin on TLR4 signaling and cardiac remodeling in an acute myocardial infarction model

초록

Acute myocardial infarction (AMI) triggers adverse cardiac remodeling through Toll-like receptor 4 (TLR4)–mediated inflammatory pathways. This study aimed to evaluate a dual-inhibition strategy targeting both extracellular and intracellular TLR4 signaling using a combination of cyclic phage display-derived inhibitory peptide 2 (cPIP2) and rosuvastatin (RSV), a clinically approved anti-inflammatory agent. In a rat AMI model, cPIP2 and RSV were administered alone or a combination of both. Pressure-volume (PV) loop analysis showed that the combined treatment significantly improved cardiac function, including increased cardiac output, stroke volume, and ejection fraction. Histological staining and RNA sequencing revealed that the dual treatment reduced fibrosis, as evidenced by decreased expression of TLR4, CD68, and IL-6 while promoting angiogenesis through upregulation of CD31. Transcriptomic analysis further revealed restoration of mitochondrial genes and inhibition of pro-inflammatory signaling pathways. These results demonstrate that concurrent extracellular and intracellular inhibition of TLR4 signaling via cPIP2 and RSV leads to robust cardiac protection and functional recovery post-AMI. This dual-targeted approach represents a promising therapeutic strategy for preventing pathological remodeling and enhancing myocardial repair after ischemic injury. © 2025 Elsevier B.V., All rights reserved.

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