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Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound
Title
Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound: antifibrotic drug.
Creator
Stefanovic, Branko, Manojlovic, Zarko, Vied, Cynthia, Badger, Crystal-Dawn, Stefanovic, Lela
Abstract/Description
Fibrosis is characterized by excessive production of type I collagen. Biosynthesis of type I collagen in fibrosis is augmented by binding of protein LARP6 to the 5’ stem-loop structure (5’SL), which is found exclusively in type I collagen mRNAs. A high throughput screen was performed to discover inhibitors of LARP6 binding to 5’SL, as potential antifibrotic drugs. The screen yielded one compound (C9) which was able to dissociate LARP6 from 5’ SL RNA in vitro and to inactivate the binding of...
Show moreFibrosis is characterized by excessive production of type I collagen. Biosynthesis of type I collagen in fibrosis is augmented by binding of protein LARP6 to the 5’ stem-loop structure (5’SL), which is found exclusively in type I collagen mRNAs. A high throughput screen was performed to discover inhibitors of LARP6 binding to 5’SL, as potential antifibrotic drugs. The screen yielded one compound (C9) which was able to dissociate LARP6 from 5’ SL RNA in vitro and to inactivate the binding of endogenous LARP6 in cells. Treatment of hepatic stellate cells (liver cells responsible for fibrosis) with nM concentrations of C9 reduced secretion of type I collagen. In precision cut liver slices, as an ex vivo model of hepatic fibrosis, C9 attenuated the profibrotic response at 1 μM. In prophylactic and therapeutic animal models of hepatic fibrosis C9 prevented development of fibrosis or hindered the progression of ongoing fibrosis when administered at 1 mg/kg. Toxicogenetics analysis revealed that only 42 liver genes changed expression after administration of C9 for 4 weeks, suggesting minimal off target effects. Based on these results, C9 represents the first LARP6 inhibitor with significant antifibrotic activity.
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Date Issued
2019/01/23
Identifier
FSU_libsubv1_scholarship_submission_1550162176_d38b7a2e, 10.1038/s41598-018-36841-y
Format
Citation
Myosin Rod Hypophosphorylation and CB Kinetics in Papillary Muscles from a TnC-A8V KI Mouse Model.
Title
Myosin Rod Hypophosphorylation and CB Kinetics in Papillary Muscles from a TnC-A8V KI Mouse Model.
Creator
Kawai, Masataka, Johnston, Jamie R, Karam, Tarek, Wang, Li, Singh, Rakesh K, Pinto, Jose R
Abstract/Description
The cardiac troponin C (TnC)-A8V mutation is associated with hypertrophic and restrictive cardiomyopathy (HCM and RCM) in human and mice. The residue affected lies in the N-helix, a region known to affect Ca-binding affinity to the N-terminal domain. Here we report on the functional effects of this mutation in skinned papillary muscle fibers from homozygous knock-in TnC-A8V mice. Muscle fibers from left ventricle were activated at 25°C under the ionic conditions of working cardiomyocytes. The...
Show moreThe cardiac troponin C (TnC)-A8V mutation is associated with hypertrophic and restrictive cardiomyopathy (HCM and RCM) in human and mice. The residue affected lies in the N-helix, a region known to affect Ca-binding affinity to the N-terminal domain. Here we report on the functional effects of this mutation in skinned papillary muscle fibers from homozygous knock-in TnC-A8V mice. Muscle fibers from left ventricle were activated at 25°C under the ionic conditions of working cardiomyocytes. The pCa-tension relationship showed a 3× increase in Ca-sensitivity and a decrease (0.8×) in cooperativity (n) in mutant fibers. The elementary steps of the cross-bridge (CB) cycle were investigated by sinusoidal analysis. The ATP study revealed that there is no significant change in the affinity of ATP (K) for the myosin head. In TnC-A8V mutant fibers, the CB detachment rate (k) and its equilibrium constant (K) increased (1.5×). The phosphate study revealed that rate constant of the force-generation step (k) decreased (0.5×), reversal step (k) increased (2×), and the phosphate-release step (1/K) increased (2×). Pro-Q Diamond staining of the skinned fibers samples revealed no significant changes in total phosphorylation of multiple sarcomeric proteins. Further investigation using liquid chromatography-tandem mass spectrometry revealed hypophosphorylation of the rod domain of myosin heavy chain in TnC-A8V mutant fibers compared to wild-type. Immunoblotting confirmed the results observed in the mass spectrometry analysis. The results suggest perturbed CB kinetics-possibly caused by changes in the α-myosin heavy chain phosphorylation profile-as a novel mechanism, to our knowledge, by which a mutation in TnC can have rippling effects in the myofilament and contribute to the pathogenesis of HCM/RCM.
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Date Issued
2017-04-25
Identifier
FSU_pmch_28445763, 10.1016/j.bpj.2017.02.045, PMC5406373, 28445763, 28445763, S0006-3495(17)30295-3
Format
Citation
Oxidative Stress in Metabolic Disorders
Title
Oxidative Stress in Metabolic Disorders: Pathogenesis, Prevention, and Therapeutics.
Creator
Yadav, Umesh C. S., Rani, Vibha, Deep, Gagan, Singh, Rakesh K., Palle, Komaraiah
Date Issued
2016
Identifier
FSU_libsubv1_wos_000370289100001, 10.1155/2016/9137629
Format
Citation