Evaluation of Nuclear Receptor Stimulation as a New Option for Cardiac Transplant Vasculopathy Prevention

Objectives: The nuclear receptor NR4A1 is reported to mediate anti-inflammatory and antiproliferative effects. Its expression was observed in cells, which also play important roles in transplant vasculopathy (TV): endothelial cells, vascular smooth muscle cells (VSMCs), and monocytes/macrophages. TV is characterized by inflammation (accumulation of inflammatory cells like lymphocytes and macrophages in the vessel wall) and proliferation (neointima formation as a result of VSMC proliferation) and therefore the stimulation of NR4A1 with the agonist cytosporone B (Csn-B) seemed a promising approach to limit TV development and we evaluated this hypothesis in a mouse model.

Methods: To analyze the influence of NR4A1-agonism on TV development, we used the mouse model of allogeneic aortic transplantation with C57BL/6 (H2b) donors and CBA (H2k) recipients. Transplanted animals were daily treated with Csn-B 10 mg/kg/d or vehicle (DMSO) (n = 8 per group). Intimal proliferation was measured as an indicator for TV. Additionally, the cellular composition of the vessel wall (VSMCs, macrophages) as well as expression of NR4A1 and inflammatory cytokines was evaluated by immunohistology or PCR, respectively.

Result: Intimal proliferation (measured as aortic lumen occlusion) was not influenced by Csn-B [50.5 ± 5.9% vs. 46.1 ± 11.4% (control); p = 0.38] and the amount of intimal VSMCs (measured as SM-MHC (= smooth muscle-myosin heavy chain) expression; [69.6 ± 4.7% of neointimal area vs. 72.3 ± 6.5% (control)]; p = 0.23), intimal macrophages (measured as F4/80 expression; [20.8 ± 7.4% of neointimal area vs. 23.4 ± 4.6% (control)]; p = 0.31) and intimal NR4A1 expression [45.5 ± 10.2% of neointimal area versus 49.4 ± 15.4% (control); p = 0.38] did not differ between Csn-B and control group. Equally, no effect of Csn-B treatment on mRNA expression of several inflammatory cytokines could be found.

Conclusion: Though anti-inflammatory and antiproliferative effects for NR4A1 activation were reported in previous studies, no influence of Csn-B treatment on TV development in our mouse model could be observed.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
19 February 2021