Human Relaxin‐2 Fusion Protein Treatment Prevents and Reverses Isoproterenol‐Induced Hypertrophy and Fibrosis in Mouse Heart

Abstract

Background Heart failure is one of the leading causes of death in Western countries, and there is a need for new therapeutic approaches. Relaxin‐2 is a peptide hormone that mediates pleiotropic cardiovascular effects, including antifibrotic, angiogenic, vasodilatory, antiapoptotic, and anti‐inflammatory effects in vitro and in vivo. Methods and Results We developed RELAX 10, a fusion protein composed of human relaxin‐2 hormone and the Fc of a human antibody, to test the hypothesis that extended exposure of the relaxin‐2 peptide could reduce cardiac hypertrophy and fibrosis. RELAX 10 demonstrated the same specificity and similar in vitro activity as the relaxin‐2 peptide. The terminal half‐life of RELAX 10 was 7 days in mouse and 3.75 days in rat after subcutaneous administration. We evaluated whether treatment with RELAX 10 could prevent and reverse isoproterenol‐induced cardiac hypertrophy and fibrosis in mice. Isoproterenol administration in mice resulted in increased cardiac hypertrophy and fibrosis compared with vehicle. Coadministration with RELAX 10 significantly attenuated the cardiac hypertrophy and fibrosis compared with untreated animals. Isoproterenol administration significantly increased transforming growth factor β1 (TGF‐β1)–induced fibrotic signaling, which was attenuated by RELAX 10. We found that RELAX 10 also significantly increased protein kinase B/endothelial NO synthase signaling and protein S‐nitrosylation. In the reversal study, RELAX 10‐treated animals showed significantly reduced cardiac hypertrophy and collagen levels. Conclusions These findings support a potential role for RELAX 10 in the treatment of heart failure.

Diverse functions of insulin-like 3 peptide

“…Studies of the effect of INSL3 injections on testicular functions in rats have shown that INSL3 can pass through the blood-testis barrier (Anand- Ivell et al 2009) and protect against GnRH antagonist-induced apoptosis in germ cells (Kawamura et al 2004). Various approaches previously used to improve the stability of relaxin (Muppidi et al 2019, Nagorniewicz et al 2019, Sun et al 2019 can be applied to INSL3 to design biologicals with the full spectrum of INSL3/RXFP2 downstream signaling. Alternatively, small molecule agonists have proven to be an attractive alternative to therapies with peptide ligands due to improved stability and potential oral bioavailability.…”

Norcantharidin induces ferroptosis via the suppression of NRF2/HO‑1 signaling in ovarian cancer cells

“…All procedures were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC ID: 17-3256) at Nantong University and performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals. Briefly, the mice were anesthetized with isoflurane (Sigma-Aldrich; Merck KGaA) inhalation at a concentration of 2.5% for anesthetic induction and then at 1.5% for anesthetic maintenance (22)(23)(24). SKOV3 cells (10 6 cells per mouse in 100 µl PBS) were implanted subcutaneously into the right flanks of 6-to 8-week-old female nu/nu mice.…”

Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

“…However, relaxin recently failed to reach its primary endpoint in a phase III clinical trial for acute heart failure 91 . The clinical success of relaxin may be limited due to its short plasma half-life 92 , and several groups have developed lipid and Fc conjugates with relaxin to extend the persistence of exposure in plasma 93 , 94 . An additional concern that may have precluded clinical pursuit of relaxin for anti-cancer treatment is the observation that relaxin signaling is involved in tumor progression and metastasis in several cancers 95 , 96 .…”