Abstract 19420: Selective Relaxin Receptor 1 Agonist (ML290) Attenuates Myocardial Ischemic Injury Through Preservation of Mitochondrial Function
Background: Treatment with recombinant human relaxin, which binds to its cognate receptor RXFP1, has been shown to attenuate myocardial infarction (MI) in animal models. Whether reperfusion therapy with the first potent and selective small-molecule agonist of RXFP1 (ML290, identified by Probe Reports; NIH Molecular Libraries Program) reduces myocardial infarct size and preserves mitochondrial and cardiac function following MI is unknown.
Methods and Results: After baseline echocardiography, adult male mice underwent MI by coronary artery ligation for 30 minutes followed by 24 h reperfusion. Mice were treated with ML290 (30 mg/Kg; ip) or vehicle (10% DMSO in saline) 5 minutes before reperfusion. ML290 significantly reduced infarct size, measured with TTC staining, and plasma cardiac troponin levels (Figs. A & B); preserved LV ejection fraction and markedly improved segmental contractile function using high sensitivity speckle tracking echocardiography (Fig. C) at 24 h post MI compared to vehicle-treated mice. Mitochondria were isolated from LV free wall at 24 h post MI in both groups to assess oxidative phosphorylation (OXPHOS, nAO/mg/min) and calcium retention capacity (CRC, nmol Ca2+/mg). Compared to untreated hearts, ML290 improved the rate of OXPHOS using glutamate (Glu) + malate (Mal) as complex I substrates (493±30 vs. control: 403±21, n=4, P<0.05), but not with succinate as complex II substrates, indicating that ML290 treatment protected complex I during myocardial ischemia/reperfusion. ML290 also tended to improve CRC (730±50 vs. control: 570±57, P=NS) in mitochondria following MI, suggesting that ML290 decreased mitochondrial permeability transition pore (MPTP) opening during reperfusion.
Conclusion: Reperfusion therapy with ML290 improves LV function at 24 h post MI and significantly reduces infarct size, possibly by improving OXPHOS and inhibiting MPTP opening. We propose that RXFP1 agonists can be promising therapeutic tools for acute MI.
Author Disclosures: C. Cain: None. A.G. Mauro: None. J. Thompson: None. J. He: None. S. Toldo: None. A. Das: None. E.J. Lesnefsky: None. F.N. Salloum: Research Grant; Significant; Investigator-Initiated Trials from Novartis.
- © 2016 by American Heart Association, Inc.