Enhanced vasoactive intestinal peptide signaling prevents the development of Duchenne muscular dystrophy-associated cardiomyopathy through inhibition of NF-κB signaling

Cardiac function was assessed weekly by echocardiography, and hearts were collected at 14 weeks of age for histological and molecular analyses. High-dose PB1046 treatment preserved cardiac function and reduced fibrosis in mdx:Utrn+/- mice. Bulk RNA sequencing analysis of cardiomyocytes isolated from mdx:Utrn+/- mice treated with high-dose PB1046 revealed an upregulation of cAMP-associated transcripts and a downregulation of NF-κB pathway genes.

The activation of cAMP signaling was confirmed by elevated cardiac cAMP levels and increased phosphorylation of nuclear CREB in mdx:Utrn+/- mice treated with high-dose PB1046. Nuclear phosphorylation of p65 was significantly reduced, suggesting that NF-κB signaling was suppressed. Together, these results indicate that activation of VIP signaling protects against cardiac dysfunction in a murine model of DMD, likely through inhibition of NF-κB signaling pathways.