Suppression of inflammation and fibrosis using soluble epoxide hydrolase inhibitors enhances cardiac stem cell-based therapy

Abstract

Stem cell replacement offers a great potential for cardiac regenerative therapy. However, one of the critical barriers to stem cell therapy is a significant loss of transplanted stem cells from ischemia and inflammation in the host environment. Here, we tested the hypothesis that inhibition of the soluble epoxide hydrolase (sEH) enzyme using sEH inhibitors (sEHIs) to decrease inflammation and fibrosis in the host myocardium may increase the survival of the transplanted human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) in a murine postmyocardial infarction model. A specific sEHI (1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea [TPPU]) and CRISPR/Cas9 gene editing were used to test the hypothesis. TPPU results in a significant increase in the retention of transplanted cells compared with cell treatment alone. The increase in the retention of hiPSC-CMs translates into an improvement in the fractional shortening and a decrease in adverse remodeling. Mechanistically, we demonstrate a significant decrease in oxidative stress and apoptosis not only in transplanted hiPSC-CMs but also in the host environment. CRISPR/Cas9-mediated gene silencing of the sEH enzyme reduces cleaved caspase-3 in hiPSC-CMs challenged with angiotensin II, suggesting that knockdown of the sEH enzyme protects the hiPSC-CMs from undergoing apoptosis. Our findings demonstrate that suppression of inflammation and fibrosis using an sEHI represents a promising adjuvant to cardiac stem cell-based therapy. Very little is known regarding the role of this class of compounds in stem cell-based therapy. There is consequently an enormous opportunity to uncover a potentially powerful class of compounds, which may be used effectively in the clinical setting. Padmini Sirish and Phung N. Thai contributed equally to the work.

The Critical Roles of Proteostasis and Endoplasmic Reticulum Stress in Atrial Fibrillation

“…While several of the COX and LOX metabolites are proinflammatory and have been studied in detail, underpinned by the translation of inhibitors of these enzymatic pathways demonstrated by aspirin and zileuton in the treatment of inflammatory diseases, the translational manipulation of the CYP450 pathway remains unexplored and underutilized clinically. The CYP450 epoxidized products, the epoxyeicosatrienoic acids (EETs) have been shown to have anti-inflammatory with several cardioprotective effects ( Li et al, 2009 , 2011 ; Liu et al, 2010 ; Qiu et al, 2011 ; Sirish et al, 2013 , 2020 ). EETs function primarily as autocrine and paracrine effectors in the cardiovascular system and kidney ( Roman et al, 2000 ; Schmelzer et al, 2005 ).…”

Chronic Diclofenac Exposure Increases Mitochondrial Oxidative Stress, Inflammatory Mediators, and Cardiac Dysfunction

“…However, DIC not only inhibits the COX-1 and COX-2 enzymes, but also affects other pathways including LOX and CYP450 leading to a decrease in the cardioprotective anti-inflammatory metabolites [44]. We have extensively shown that EETs, the CYP450 metabolites, are anti-inflammatory and cardioprotective in preventing ventricular hypertrophy, electrical remodeling, and cardiac fibrosis and reducing both atrial and ventricular arrhythmia inducibility in cardiac hypertrophy and MI models [19,20,45]. Our results in this study demonstrate a decrease in EETs isomers with DIC treatment (Figure S3A) suggesting a reduction in cardioprotection with DIC treatment.…”

Activating endogenous resolution pathways by soluble epoxide hydrolase inhibitors for the management of COVID‐19

“…Furthermore, inhibition of sEH has been used to treat rheumatoid arthritis by reducing nociception and inflammation, [ 67 ] to reduce inflammation and fibrosis in the host myocardium by inhibiting sEH, [ 68 ] and to improve vascular repair in the treatment of Kawasaki disease by inhibiting sEH. [ 69 ] sEH inhibitors have recently been shown to be effective in the treatment of sepsis.…”

“…Furthermore, TPPU decreased local proinflammatory cytokine concentrations while increasing the levels of the anti‐inflammatory cytokine interleukin‐10 in TMJ tissue. [ 68 ] TPPU was found to decrease inflammation and fibrosis in another trial, making it a promising adjuvant to cardiac stem cell treatment. [ 69 ] In a recent study, TPPU and EC5026 were found to inhibit neuroinflammation in the central nervous system of a lipopolysaccharide‐induced mouse model.…”