Exogenous Ang-1 enhances perfusion in hypoperfused tissues only in the presence of increased levels of endogenous VEGF. Overexpression of VEGF, however, after causing an inflammatory response, does not improve collateral blood flow.

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.

Inflammation plays a central role in atherogenesis. It was hypothesized that infection of apolipoprotein E-deficient mice with murine cytomegalovirus (MCMV) increases serum levels of proinflammatory cytokines, which may induce "proatherosclerotic" changes in endothelial cells (ECs). Serum samples were collected from uninfected and infected mice. ELISA was used to determine cytokine serum levels and monocyte chemoattractant protein-1 (MCP-1) levels in the supernatant of mouse ECs incubated with serum-containing medium. Serum samples from infected mice induced MCP-1 expression by ECs. These serum samples contain interferon (IFN)-gamma, whereas IFN-gamma was undetectable in serum samples from uninfected mice. Preincubating infected mouse serum with anti-IFN-gamma monoclonal antibody significantly decreased serum-induced EC expression of MCP-1. Thus, MCMV infection increases IFN-gamma serum levels, such serum can induce MCP-1 in ECs, and the serum-induced MCP-1 expression is due, at least in part, to IFN-gamma. If these changes in EC function also occur in vivo in response to infection, they could exacerbate atherogenesis.

Exogenous Ang-1 enhances perfusion in hypoperfused tissues only in the presence of increased levels of endogenous VEGF. Overexpression of VEGF, however, after causing an inflammatory response, does not improve collateral blood flow.

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