Location: Exhibit/Poster Hall A-B - Pennsylvania Convention Center
Poster Board Number: E72
Jamie Francisco (Rutgers New Jersey Medical School), Yu Zhang (Rutgers New Jersey Medical School), Yasuki Nakada (Rutgers New Jersey Medical School), Che-Ming Hu (Institute of Biomedical Sciences, Academia Sinica), Peiyong Zhai (Rutgers New Jersey Medical School), Dominic Del Re (Rutgers New Jersey Medical School)
Presenting Author Rutgers New Jersey Medical School
Inflammation is an integral component of cardiovascular disease and is thought to contribute to cardiac dysfunction in ischemic and non-ischemic models of heart failure. While ischemia-induced inflammation has been extensively studied in the heart, relatively less is known regarding cardiac inflammation during non-ischemic stress. Recent work has implicated a role for Yes-associated protein (YAP), a transcription co-factor, in modulating cardiac inflammation in response to ischemic injury; however, whether YAP influences inflammation in the heart during non-ischemic stress is not described. We hypothesized that YAP mediates a pro-inflammatory response during pressure overload (PO)-induced non-ischemic injury, and that targeted YAP inhibition in the myeloid compartment is cardioprotective. In mice, PO elicits an immune response characterized by infiltration of myeloid cells that precedes cardiac dysfunction. Myeloid cells isolated from the heart after 7 days PO showed evidence of increased YAP activity. Myeloid-specific YAP knockout mice (YAPF/F;LysMCre) were subjected to PO stress. After 4 weeks, cardiac hypertrophy was similar between myeloid YAP KO mice and controls. However, systolic dysfunction, cardiac fibrosis, apoptosis, “fetal gene” induction, and additional indicators of pathological remodeling were attenuated in myeloid YAP KO mice compared to controls. Additionally, inflammatory gene expression and CCR2+ macrophage infiltration in the myocardium were significantly attenuated in myeloid YAP KO mice after PO, indicating reduced inflammation compared to controls. Conversely, angiogenic indicators and pro-resolving genes were enhanced in myeloid YAP KO hearts. Experiments using primary bone marrow-derived macrophages (BMDMs) from YAP KO and control mice demonstrated that YAP suppression attenuated “M1-like” inflammatory gene expression, while “M2-like” resolving genes were augmented following stimulation. The inflammasome is a multiprotein complex and important facilitator of cytokine processing that mediates inflammation in the injured heart. We observed attenuated inflammasome priming and function in YAP deficient BMDMs, as well as in myeloid YAP KO hearts following PO, indicating disruption of inflammasome induction. Finally, we leveraged nanoparticle-mediated delivery of the YAP inhibitor verteporfin to test the translational potential of targeting YAP to prevent heart failure. An alternate-day dosing regimen of drug-loaded nanoparticles attenuated inflammation and fibrosis, and improved myocardial capillary density after 2 weeks PO compared to DMSO nanoparticle control treatment. Together these data implicate myeloid YAP as an important molecular nodal point that facilitates cardiac inflammation and pathology during PO stress and suggest that selective inhibition of YAP may prove a novel therapeutic target in non-ischemic heart disease.
Support or Funding Information
This work was supported by grants from the National Institutes of Health and the American Heart Association.
