Therapeutic Approaches for Treatment of Age-associated Chronic Inflammation

National Institute On Aging

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Abstract

The broad objective of this program is to perform preclinical experimentation on animal models of aging and chronic inflammation to elucidate the mechanisms of its development and to evaluate the potential of different therapeutic modalities to limit the extent of chronic inflammation induced damage and to prevent or attenuate the development of aging and age-associated disorders in cardiovascular system. ARA290 is a novel anti-inflammatory peptide. ARA290, a non-erythropoietic peptide, simulates a part of the erythropoietin (EPO) molecule. We are examining the effect of ARA290 in multiple tissues, including heart, arteries, skeletal muscle, brain, pancreas, liver and blood. Our hypothesis is that chronic administration of ARA290 will reduce widespread tissue inflammation associated with aging and thus will alter the course of aging.18-mo-old F344BN male rats (n=200) have been randomized into treatment and placebo groups and IP injections 3times/week. Preliminary results indicated that ARA290 increased the ROS threshold for mitochondrial membrane permeability transition (mPTP) induction through PI3k/Akt pathway. GSK-3&#946; has emerged as the integration point of many pathways and plays a central role in transferring protective signals downstream to target(s) that act at or in proximity to the mPTP. After 10 min exposure to ARA290, GSK3&#946; is inhibited by phosphorylation on Ser9 in LPS-treated macrophage cells. This pilot data indicated that one hour after a 10 min exposure to either EPO or ARA290, the mPTP-ROS threshold in cardiomyocytes from 3-month old rats was increased by 40-45% compared to time-matched controls. The ability of wortmannin to block these effects indicates an involvement of PI3K/AKT/GSK3&#946; cascade. Since the apparent serum half-life of ARA290 has been measured to be on the order of just several minutes while the presumptive cellular responses in various target tissues apparently extend for hours to days beyond that, we sought to examine the existence (and duration) of the memory of the signals activated on the exposed target tissues. In particular, note that the response of the mPTP-ROS threshold in rat cardiomyocytes to a short duration (10 min) exposure to ARA290 persists for several hours following ARA290 removal. Our preliminary results also showed that ARA290 delays age-associated functional changes in heart and vessels in aged rats. Male, 20-month old, Fisher344 rats (n=34) received either ARA290 (70ug/kg/day; n=12) or saline (n=12) via implanted mini-osmotic pumps for 3 months, or were sacrificed to assess baseline parameters (n=10). ARA290 did not affect age-associated mortality or weight loss. Repeated echocardiography, however, showed that left ventricular (LV) ejection fraction (EF) was increased (p<0.05) by ARA290 in saline-treated controls. Invasive hemodynamic measurements revealed that ARA290 did not affect the blood pressure, but preserved arterio-ventricular coupling, the ratio of arterial elastance (Ea) to LV end-systolic elastance (Ees) and Ea/Ees, which reflects the efficiency of energy transfer between heart and vessels during heartbeat. In rats that received saline, pulse wave velocity (PWV) increased by 34% from the baseline value, while in rats that received ARA290, PWV increased by only 15%. Also, myocardial Interstitial Collagen and macrophage infiltration increased in saline-treated rats and were reduced by ARA290.