Linda L. Johnson
Parke-Davis
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Featured researches published by Linda L. Johnson.
Circulation | 2001
J.Thomas Peterson; Hussein Hallak; Linda L. Johnson; Hua Li; Patrick M. O’Brien; Drago Robert Sliskovic; Thomas M.A. Bocan; Mytsi L. Coker; Takuma Etoh; Francis G. Spinale
BackgroundMatrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure. Methods and ResultsLV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n=10), (2) SHHF at 13 months (n=12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg · kg−1 · d−1 PO; n=14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n=12), and (5) WF at 13 months (n=12). Plasma concentrations of the MMP inhibitor (116±11 &mgr;mol/L) reduced in vitro LV myocardial MMP-2 activity by ≈100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578±477 versus 5983±109 mm Hg/s, P ≤0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443±12 versus 563±33 mL, P ≤0.05) and increased further by 13 months (899±64 mL, P ≤0.05). LV myocardial MMP-2 activity was increased by ≈2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak +dP/dt was similar to WF values and LV volume was reduced compared with untreated SHHF values (678±28 mL, P ≤0.05). ConclusionsMMP activity contributes to LV dilation and progression to LV dysfunction in a rodent HF model, and direct MMP inhibition can attenuate this process.
Biochemical and Biophysical Research Communications | 1992
Qi Zhuang Ye; Linda L. Johnson; Vijaykumar M. Baragi
The gene for PUMP (putative metalloproteinase), a human matrix metalloproteinase, was synthesized by a PCR-based method. The DNA fragment of 546 bases containing the PUMP gene was generated by overlap extension of six long oligonucleotides (length ranging from 101 to 116 bases) and subsequent amplification by two short terminal oligonucleotide primers (length from 20 to 48 bases) in one pot without using restriction and ligation enzymes. The synthetic gene was cloned into a T7 expression vector in two ways to express PUMP as a non-fusion protein. Both constructs showed high level expression in E. coli.
Journal of Biological Chemistry | 1999
Linda L. Johnson; Dirk A. Bornemeier; Jeffrey A. Janowicz; Jing Chen; Alexander Pavlovsky; Daniel F. Ortwine
For an animal model to predict a compound’s potential for treating human disease, inhibitor interactions with the cognate enzymes of separate species must be comparable. Rabbit and human isoforms of stromelysin-1 are highly homologous, yet there are clear and significant compound-specific differences in inhibitor potencies between these two enzymes. Using crystal structures of discordant inhibitors complexed with the human enzyme, we generated a rabbit enzyme homology model that was used to identify two unmatched residues near the active site that could explain the observed disparities. To test these observations, we designed and synthesized three chimeric mutants of the human enzyme containing the single (H224N and L226F) and double (H224N/L226F) mutations. A comparison of inhibitor potencies among the mutant and wild-type enzymes shows that the mutation of a single amino acid in the human enzyme, histidine 224 to asparagine, is sufficient to change the selectivity profile of the mutant to that of the rabbit isoform. These studies emphasize the importance of considering species differences, which can result from even minor protein sequence variations, for the critical enzymes in an animal disease model. Homology modeling provides a tool to identify key differences in isoforms that can significantly affect native enzyme activity.
Journal of Biological Chemistry | 1987
Oksana Lockridge; Cynthia F. Bartels; Theresa A. Vaughan; Cassandra K. Wong; Sheila E. Norton; Linda L. Johnson
Journal of Biological Chemistry | 1996
J. Michael Shipley; Glenn A. R. Doyle; Catherine J. Fliszar; Qi Zhuang Ye; Linda L. Johnson; Steven D. Shapiro; Howard G. Welgus; Robert M. Senior
Structure | 1996
Venugopal Dhanaraj; Qi Zhuang Ye; Linda L. Johnson; Donald Hupe; Daniel F. Ortwine; James B. Dunbar; J. R. Rubin; Alexander Pavlovsky; Christine Humblet; Tom L. Blundell
Journal of Medicinal Chemistry | 2000
Patrick Michael O'brien; Daniel F. Ortwine; Alexander Pavlovsky; Joseph Armand Picard; Drago Robert Sliskovic; Bruce David Roth; Richard D. Dyer; Linda L. Johnson; Chiu Fai Man; Hussein Hallak
Biochemistry | 1992
Qi Zhuang Ye; Linda L. Johnson; Donald Hupe; Vijaykumar M. Baragi
Journal of Biological Chemistry | 2000
Linda L. Johnson; Alexander Pavlovsky; Adam R. Johnson; Jeffrey A. Janowicz; Chiu Fai Man; Daniel F. Ortwine; Claude Forsey Purchase; Andrew D. White; Donald Hupe
Croatica Chemica Acta | 1999
Venugopal Dhanaraj; Mark G. Williams; Qi Zhuang Ye; Franck Molina; Linda L. Johnson; Daniel F. Ortwine; Alexander Pavlovsky; J. Ron Rubin; Richard W. Skeean; Andrew David White; Christine Humblet; Donald Hupe; Tom L. Blundell