Ivabradine alleviates the cisplatin-induced cardiotoxicity in rats through regulating the crosstalk between MLCP/PKG, MEK/ERK pathways and miRNA-34a levels
Year: 2026
Type: article
Abstract: BACKGROUND: Ivabradine (IVA), a broad-spectrum hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitor, improves cardiac function in cardiovascular diseases and may protect against drug-induced cardiotoxicity. This study investigated the cardioprotective effects of IVA against cisplatin (Cis)-induced cardiac injury and explored the underlying molecular mechanisms. METHODS: Rats received IVA (5 mg/kg, orally) for 28 consecutive days and Cis (7.5 mg/kg, intraperitoneally) on day 5. Cardiac oxidative stress biomarkers, inflammatory cytokines, histopathological alterations, and molecular signaling pathways were evaluated using biochemical assays, H&E staining, western blotting, PCR, and immunohistopathology. RESULTS: IVA markedly improved cardiac histoarchitecture and attenuated Cis-induced pathological alterations. It exerted antioxidant and anti-inflammatory effects by reducing malondialdehyde (MDA), NADPH oxidase, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 levels, while increasing superoxide dismutase (SOD), IL-10, and endothelial nitric oxide synthase (eNOS). IVA downregulated cAMP response element-binding protein (CREB), extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase kinase (MEK), protein kinase C-epsilon (PKCε), and microRNA-34a (miRNA-34a), while upregulating protein kinase G (PKG), myosin light chain phosphatase (MLCP), and rapidly accelerated fibrosarcoma-1 (Raf-1). Furthermore, IVA enhanced cardiac cell survival, as evidenced by increased B-cell lymphoma 2 (Bcl-2) expression and reduced caspase-3 immunostaining. CONCLUSION: IVA significantly attenuates Cis-induced cardiotoxicity through antioxidant, anti-inflammatory, anti-apoptotic, and miRNA-34a-mediated mechanisms involving multiple cardioprotective signaling pathways.
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7172291710