Ccn2 Deletion Reduces Cardiac Dysfunction, Oxidative Markers, and Fibrosis Induced by Doxorubicin Administration in Mice

• Published in: International journal of molecular sciences 2024-09, Vol.25 (17), p.9617
• Main Authors: Tejera-Muñoz, Antonio, Cortés, Marcelino, Rodriguez-Rodriguez, Alianet, Tejedor-Santamaria, Lucia, Marchant, Vanessa, Rayego-Mateos, Sandra, Gimeno-Longas, Maria José, Leask, Andrew, Nguyen, Tri Q, Martín, María, Tuñón, Jose, Rodríguez, Isabel, Ruiz-Ortega, Marta, Rodrigues-Díez, Raul R
• Format: Article
• Language: English
• Subjects: Aneurysms; Animals; Apoptosis; Atherosclerosis; Biomarkers; cardiac dysfunction; Cardiac function; Cardiomyocytes; Cardiotoxicity; Cardiotoxicity - genetics; Cardiotoxicity - metabolism; CCN2; Communication; Connective Tissue Growth Factor - genetics; Connective Tissue Growth Factor - metabolism; doxorubicin; Doxorubicin - adverse effects; Fibrosis; Gene Deletion; Gene expression; Growth factors; Heart failure; Hypertension; Investigations; Ischemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium - metabolism; Myocardium - pathology; Oxidative stress; Oxidative Stress - drug effects; Proteins
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25179617

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent. To this end, we employed conditional knockout (KO) mice for the gene (CCN2-KO), which were administered DOX and compared to DOX-treated wild-type (WT) control mice. Our findings demonstrated that the ablation of CCN2 ameliorated DOX-induced cardiac dysfunction, as evidenced by improvements in ejection fraction (EF) and fractional shortening (FS) of the left ventricle. Furthermore, DOX-treated CCN2-KO mice exhibited a significant reduction in the gene expression and activation of oxidative stress markers (Hmox1 and Nfe2l2/NRF2) relative to DOX-treated WT controls. Additionally, the deletion of markedly attenuated DOX-induced cardiac fibrosis. Collectively, these results suggest that CCN2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity by modulating oxidative stress and fibrotic pathways. These findings provide a novel avenue for future investigations to explore the therapeutic potential of targeting CCN2 in the prevention of DOX-induced cardiac dysfunction.