PMID- 36711986
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240418
DP  - 2023 Jan 18
TI  - HuR inhibition reduces post-ischemic cardiac remodeling by dampening acute 
      inflammatory gene expression and the innate immune response.
LID - 2023.01.17.524420 [pii]
LID - 10.1101/2023.01.17.524420 [doi]
AB  - Myocardial ischemia/reperfusion (I/R) injury and the resulting cardiac remodeling 
      is a common cause of heart failure. The RNA binding protein Human Antigen R (HuR) 
      has been previously shown to reduce cardiac remodeling following both I/R and 
      cardiac pressure overload, but the full extent of the HuR-dependent mechanisms 
      within cells of the myocardium have yet to be elucidated. In this study, we 
      applied a novel small molecule inhibitor of HuR to define the functional role of 
      HuR in the acute response to I/R injury and gain a better understanding of the 
      HuR-dependent mechanisms during post-ischemic myocardial remodeling. Our results 
      show an early (two hours post-I/R) increase in HuR activity that is necessary for 
      early inflammatory gene expression by cardiomyocytes in response to I/R. 
      Surprisingly, despite the reductions in early inflammatory gene expression at two 
      hours post-I/R, HuR inhibition has no effect on initial infarct size at 24-hours 
      post-I/R. However, in agreement with previously published work, we do see a 
      reduction in pathological remodeling and preserved cardiac function at two weeks 
      post-I/R upon HuR inhibition. RNA-sequencing analysis of neonatal rat ventricular 
      myocytes (NRVMs) at two hours post-LPS treatment to model damage associated 
      molecular pattern (DAMP)-mediated activation of toll like receptors (TLRs) 
      demonstrates a broad HuR-dependent regulation of pro-inflammatory chemokine and 
      cytokine gene expression in cardiomyocytes. We show that conditioned media from 
      NRVMs pre-treated with HuR inhibitor loses the ability to induce inflammatory 
      gene expression in bone marrow derived macrophages (BMDMs) compared to NRVMs 
      treated with LPS alone. Functionally, HuR inhibition in NRVMs also reduces their 
      ability to induce endocrine migration of peripheral blood monocytes in vitro and 
      reduces post-ischemic macrophage infiltration to the heart in vivo. In summary, 
      these results suggest a HuR-dependent expression of pro-inflammatory gene 
      expression by cardiomyocytes that leads to subsequent monocyte recruitment and 
      macrophage activation in the post-ischemic myocardium.
FAU - Slone, Samuel
AU  - Slone S
FAU - Anthony, Sarah R
AU  - Anthony SR
FAU - Green, Lisa C
AU  - Green LC
FAU - Nieman, Michelle L
AU  - Nieman ML
FAU - Alam, Perwez
AU  - Alam P
FAU - Wu, Xiaoqing
AU  - Wu X
FAU - Roy, Sudeshna
AU  - Roy S
FAU - Aube, Jeffrey
AU  - Aube J
FAU - Xu, Liang
AU  - Xu L
FAU - Lorenz, John N
AU  - Lorenz JN
FAU - Owens, A Phillip
AU  - Owens AP
FAU - Kanisicak, Onur
AU  - Kanisicak O
FAU - Tranter, Michael
AU  - Tranter M
AUID- ORCID: 0000-0002-0609-3717
LA  - eng
GR  - 16SDG27360004/AHA/American Heart Association-American Stroke Association/United 
      States
PT  - Preprint
DEP - 20230118
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC9882229
EDAT- 2023/01/31 06:00
MHDA- 2023/01/31 06:01
PMCR- 2023/01/27
CRDT- 2023/01/30 03:57
PHST- 2023/01/30 03:57 [entrez]
PHST- 2023/01/31 06:00 [pubmed]
PHST- 2023/01/31 06:01 [medline]
PHST- 2023/01/27 00:00 [pmc-release]
AID - 2023.01.17.524420 [pii]
AID - 10.1101/2023.01.17.524420 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Jan 18:2023.01.17.524420. doi: 
      10.1101/2023.01.17.524420.