Abstract Body: Introduction: Doxorubicin (DOX) is a widely used chemotherapeutic associated with dose-dependent related cardiotoxicity, termed DRC. DRC is characterized by pronounced cardiac fibrosis leading to impaired cardiac function. The relaxin family peptide receptor 1 (RXFP1) was first identified for its role in the cardiac remodeling characteristic of pregnancy. Relaxin-2 (RLX) is the cognate hormone for RXFP1, and when infused into murine models of ischemic heart failure attenuates cardiac dysfunction. Current heart failure therapies have not proven effective in treating DRC. However, synthetic, long-acting RXFP1 agonists may represent a novel therapeutic modality given their antifibrotic, antioxidant, and anti-inflammatory effects.
Hypothesis: The RXFP1 agonist ML290 mitigates ATII and DOX-induced cardiac dysfunction and fibrosis.
Goal: To investigate the cardioprotective potential of ML290 in an in vivo model of DRC.
Methods: Humanized RXFP1 mice were implanted with an osmotic pump containing either Angiotensin II (ATII) (1500 ng/kg/day) or saline and randomized to receive either a weekly dose of 5 mg/kg DOX or saline for 4 weeks. Mice in each group were randomized to receive either ML290 (30 mg/kg) or vehicle. Cardiac function was assessed via echocardiography and blood pressure at baseline and weekly for 4 weeks. Cardiac tissue fibrosis and cell death were analyzed via picrosirius red, TUNEL stain, and immunofluorescence. Statistical significance was determined by one-way ANOVA with Tukey’s test. Error bars represent the mean ± SEM. P values denoted as *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.
Results: ATII and ATII+DOX mice experienced a 40% decline in left ventricular ejection fraction (LVEF) from baseline values by day 28 that was attenuated by ML290 treatment in both groups. ML290 also significantly attenuated ATII and ATII+DOX induced cardiac fibrosis, shown by substantial decrease in total fibrosis (PSR) and expression of Periostin, a specific marker for pathologic cardiac fibrosis. ATII alone did not induce significant increases in myocardial cell death, but ATII+DOX mice showed a 10% increase in TUNEL that was significantly reduced by ML290.
Conclusion: These findings suggest ML290 protects against both ATII and ATII+DOX related cardiotoxicity largely through attenuation of fibrosis and pathologic remodeling as well as preservation of cardiac function.