Abstract Body: Although the cardioprotective role of alpha-calcitonin gene related peptide (α-CGRP), a 37 amino acid vasodilator neuropeptide, is known for heart failure (HF) and other cardiac diseases, low bioavailability of the peptide makes it not feasible to use as a therapeutic agent. To increase the bioavailability of the peptide, our laboratory chemically synthesized an α-CGRP analog (NMEG-CGRP) containing two molecules of N-methoxyethylglycine (NMEG) peptoid at the N-terminus of human α-CGRP. Bioactivity, stability, and toxicity of NMEG-CGRP were assessed. LC-MS mass spectrometry experiments demonstrated that an α-CGRP-degrading enzyme, insulin-degrading enzyme (IDE), cleaved native α-CGRP within 30 min, while NMEG-CGRP remained intact until 1 h indicating that the addition of NMEG-peptoid makes α-CGRP a more stable peptide. NMEG-CGRP did not affect the viability of rat H9C2 cardiac myocyte cells (MTT-cell viability assay) and lowered the systolic pressure (as measured by tail-cuff blood pressure analysis system) in the wild-type mice. The cardioprotective effect of NMEG-CGRP was tested in the transverse aortic constriction (TAC) pressure-overload mouse model of HF. Male C57BL6 mice were divided into 4 groups (n= 6-7 mice): sham, sham+NMEG-CGRP, TAC, and TAC+NMEG-CGRP, and TAC protocol was performed in the respective mouse groups. Two days post-TAC, NMEG-CGRP (3.6 mg/kg/mouse) was administered subcutaneously on alternate days, for a total of 28 days, in the TAC+NMEG-CGRP and sham+NMEG-CGRP mice, and echocardiography was performed weekly to assess cardiac function. At the experimental endpoint, hearts were collected from all mouse groups. The echocardiography data demonstrated that TAC significantly lowered cardiac functions (fractional shortening, FS) in mice, however, NMEG-CGRP delivery significantly improved FS in the TAC+NMEG-CGRP mice. On day 30, the %FS (mean±SD) was: sham= 49.5±1.5, sham+NMEG-CGRP= 47.9±2.3, TAC= 28.3±3.2, and TAC+NMEG-CGRP= 40±1.5. Histological data showed that cardiac cell size, fibrosis, and apoptosis were significantly increased in TAC-mice that was significantly attenuated by NMEG-CGRP in TAC+NMEG-CGRP mice. These studies demonstrated that NMEG-CGRP is a bioactive CGRP-analog and protects the heart against HF at the pathophysiological level. Hence, NMEG-CGRP is a potential therapeutic agent to treat pressure-overload induced HF.