Abstract 14318: Sex Differences in Treatment Responses to NP-6A4, a Cardiomyopathy Drug With the FDA Designation, in Heart Disease Induced by Untreated Obesity

Abstract

Introduction: Obesity affects 42% of the US population and exacerbates heart disease. Currently there are no effective treatments for obesity-induced cardiac pathology. We reported that NP-6A4, a peptide agonist of the Angiotensin receptor AT2R mitigates cardiac dysfunction and damage in male rats with untreated obesity. Since cardiac pathology of male and female rats with untreated obesity differ, we hypothesized that there can be differences in their cardiac response to NP-6A4. Methods and Results: Echocardiographic analysis was performed in 15-week old male and female healthy Wistar (N=8) or Zucker lean (N=7) rats treated with saline, and obese and pre-diabetic Zucker rats treated with saline or NP-6A4 (1.8-10mg/kg/day in saline) for four weeks (N=8/group for females, N=7/group for males; subcutaneous delivery). Compared to healthy males, obese males showed significant (P<0.05) reduction in heart rate and increase in anterior wall thickness and left ventricular (LV) filling pressure (E/E’) suggesting concentric hypertrophy. Compared to healthy females, obese females showed significant (P<0.05) reduction in relative wall thickness, heart rate, and ejection fraction (although preserved) and increase in LV internal diameter at both diastole and systole indicating eccentric hypertrophy. NP-6A4 treatment suppressed the pathologic changes in both obese males and females (P<0.05). In another cohort of obese female rats NP-6A4 treatment from 13-to 17-weeks significantly (P<0.05) reduced abnormal E/A ratio and isovolumic contraction and relaxation time, and improved myocardial radial strain. Treatment with AT2R antagonist PD123319 (N=8: 5mg/kg/day delivered subcutaneously) abolished NP-6A4 effects. Cardiac proteome analysis of 18 tissue samples from this cohort using data independent acquisition (DIA) resulted in a total proteome of 4520 proteins and 296 differentially expressed proteins that were significant (P<0.01). Ingenuity pathway analysis predicted that inhibition of NP-6A4-mediated signaling by PD123319 may increase infection of cells (P=<0.001). Conclusion: NP-6A4 attenuated cardiac pathology induced by untreated obesity by altering different cardiac parameters in male and female rats.