Targeting E-selectin to ameliorate cardiac fibrosis and diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction
2Neufeld Cardiac Research Institute, Faculty of Medicine, Tel Aviv University, Israel
3Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
4Department of Biomedical Engineering, University of Virginia, USA
Introduction: Heart failure with preserved ejection fraction (HFpEF) is a common, deadly disease, with no effective treatment. The endothelial adhesion molecule E-selectin has been implicated in the pathogenesis of HFpEF. Circulating leukocytes bind to E-selectin and infiltrate the myocardium, causing inflammation, oxidative stress, and fibrosis, thereby impairing left ventricular (LV) relaxation and diastolic function.
Objective: To test the hypothesis that E-selectin inhibition, using an E-selectin-targeted copolymer (P-Esbp), could improve cardiac function and structure in a mouse model of HFpEF.
Methods and results: To induce HFpEF in mice, we implanted subcutaneous osmotic pumps for 28-day angiotensin-II infusion. We then administered intraperitoneal injections of (1) P-Esbp, (2) a control, non-specific copolymer (P-Scrm), or (3) saline, beginning at day 7 post-surgery.
Mice receiving weekly 0.5 mg injections of either P-Esbp, P-Scrm, or saline, developed LV hypertrophy with preserved ejection fraction, as measured by serial echocardiography studies. Ex-vivo whole heart imaging, using an IVIS® Lumina imaging system, confirmed P-Esbp accumulation in the heart (Fig. 1A). Microscopic examination confirmed specific P-Esbp targeting to cardiac endothelial cells (Fig. 1B). However, P-Esbp had no significant effect on interstitial and perivascular cardiac fibrosis, as measured by histopathology (Fig. 1C-D).
Next, we sought to determine the effect of P-Esbp on oxidative stress and diastolic function. Mice receiving two 1 mg injections per week of either P-Esbp or P-Scrm underwent serial cardiac magnetic resonance imaging studies. We detected increased levels of oxidative stress in both groups, using a new method based on the nitroxide-enhanced contrast agent 3-Carbamoyl-PROXYL (Fig. 1E). While the E/A ratio and the myocardial performance index were higher in P-Esbp-treated mice, the E/e` ratio was significantly lower, suggesting improved diastolic function (Fig. 1F-H).
Conclusions: P-Esbp targets the cardiac endothelium and improves diastolic function in a mouse model of HFpEF. Targeting E-selectin could present a new strategy for HFpEF treatment.
Figure 1.
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