Abstract 4139169: Treatment with methotrexate associated with LDL-like nanoparticles prevents the development of left ventricular fibrosis in a spontaneously hypertensive rat model

Introduction: Systemic arterial hypertension (SAH) can lead to left ventricle (LV) fibrosis and ventricular dysfunction. Methotrexate (MTX) associated with lipid nanoparticles (LDE) increases the cellular uptake of MTX by ninety-fold, which leads to therapeutic efficacy and reduces drug toxicity. Previously, treatment of rats with myocardial infarction with LDE-MTX decreased LV fibrosis and prevented ventricular dysfunction. The aim was to test LDE-MTX to preclude the development of cardiac damages caused by hypertension in spontaneously hypertensive rats (SHR). Methods: Twenty-four male rats with six-week-old were allocated in 3 groups: Control (CT): Wistar-Kyoto rats injected with saline; SHR: treated with LDE only and SHR-LDE-MTX: treated with LDE-MTX (1mg/Kg/week, I.P.). After 20 weeks of treatment, echocardiography, morphometry and protein expression were performed in the LV. The data were analyzed by ANOVA with Turkey’s post-test or Kruskal-Wallis test with Dunn's post-test. Linear regression was used to evaluate potential relationships. Results: Compared to CT, the two SHR groups showed dilation (increase in systolic and diastolic diameter); hypertrophy (increased thickness of the posterior wall) and systolic dysfunction (decreased ejection and shortening fractions). Furthermore, the SHR group showed increased LV fibrosis in both the interstitial region and the papillary muscle, possibly resulting from increased of type I collagen content. Treatment of SHR with LDE-MTX had no effect on LV dilation, hypertrophy or systolic dysfunction. However, LDE-MTX decreased LV fibrosis of the interstitial region and the papillary muscle. In addition, LDE-MTX increased the expression of MMP-2, and increased the bioavailability of intracellular adenosine, via increased expression of the adenosine A3 receptor. There was a negative correlation between the expression of the adenosine A3 receptor with interstitial fibrosis (r2=-0.31, p=0.03) and papillary muscle (r2=-0.47, p=0.03), indicating that the increased bioavailability of intracellular adenosine also contributed to the decrease in LV fibrosis in SHR. Conclusion: In SHR, treatment with LDE-MTX reduced LV fibrosis, possibly by modulating MMP-2 expression and increasing the bioavailability of intracellular adenosine, via the adenosine A3 receptor. These results suggest a therapeutic role for LDE-MTX in patients with LV fibrosis and heart failure caused by SAH, to be explored in future clinical studies.