7 research outputs found
Cardiomyocyte and vascular smooth muscle independent 11Ī²-hydroxysteroid dehydrogenase 1 amplifies infarct expansion, hypertrophy and the development of heart failure following myocardial infarction in male mice
Global deficiency of 11Ī²-hydroxysteroid dehydrogenase type 1 (11Ī²-HSD1), an enzyme that regenerates glucocorticoids within cells, promotes angiogenesis, and reduces acute infarct expansion after myocardial infarction (MI), suggesting that 11Ī²-HSD1 activity has an adverse influence on wound healing in the heart after MI. The present study investigated whether 11Ī²-HSD1 deficiency could prevent the development of heart failure after MI and examined whether 11Ī²-HSD1 deficiency in cardiomyocytes and vascular smooth muscle cells confers this protection. Male mice with global deficiency in 11Ī²-HSD1, or with Hsd11b1 disruption in cardiac and vascular smooth muscle (via SM22Ī±-Cre recombinase), underwent coronary artery ligation for induction of MI. Acute injury was equivalent in all groups. However, by 8 weeks after induction of MI, relative to C57Bl/6 wild type, globally 11Ī²-HSD1-deficient mice had reduced infarct size (34.7 Ā± 2.1% left ventricle [LV] vs 44.0 Ā± 3.3% LV, P = .02), improved function (ejection fraction, 33.5 Ā± 2.5% vs 24.7 Ā± 2.5%, P = .03) and reduced ventricular dilation (LV end-diastolic volume, 0.17 Ā± 0.01 vs 0.21 Ā± 0.01 mL, P = .01). This was accompanied by a reduction in hypertrophy, pulmonary edema, and in the expression of genes encoding atrial natriuretic peptide and Ī²-myosin heavy chain. None of these outcomes, nor promotion of periinfarct angiogenesis during infarct repair, were recapitulated when 11Ī²-HSD1 deficiency was restricted to cardiac and vascular smooth muscle. 11Ī²-HSD1 expressed in cells other than cardiomyocytes or vascular smooth muscle limits angiogenesis and promotes infarct expansion with adverse ventricular remodeling after MI. Early pharmacological inhibition of 11Ī²-HSD1 may offer a new therapeutic approach to prevent heart failure associated with ischemic heart disease
T cell depletion protects against alveolar destruction due to chronic cigarette smoke exposure in mice
A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit
Characterization of the Potent, Selective Nrf2 Activator, 3-(Pyridin-3-Ylsulfonyl)-5-(Trifluoromethyl)-2 H
Implementing Project Delivery Process Improvements: Identification of Resistance Types and Frequencies
Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2āRelated Factor 2 (KEAP1:NRF2) ProteināProtein Interaction with High Cell Potency Identified by Fragment-Based Discovery
KEAP1
is the key regulator of the NRF2-mediated cytoprotective
response, and increasingly recognized as a target for diseases involving
oxidative stress. Pharmacological intervention has focused on molecules
that decrease NRF2-ubiquitination through covalent modification of
KEAP1 cysteine residues, but such electrophilic compounds lack selectivity
and may be associated with off-target toxicity. We report here the
first use of a fragment-based approach to directly target the KEAP1
KelchāNRF2 interaction. X-ray crystallographic screening identified
three distinct āhot-spotsā for fragment binding within
the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment
hit to molecules with nanomolar affinity for KEAP1 while maintaining
drug-like properties. This work resulted in a promising lead compound
which exhibits tight and selective binding to KEAP1, and activates
the NRF2 antioxidant response in cellular and <i>in vivo</i> models, thereby providing a high quality chemical probe to explore
the therapeutic potential of disrupting the KEAP1āNRF2 interaction