PubMed · 5642259
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J P Benhamou, J Caroli, C Debray, L Leger. 1968-03-09. [Phalloides hepatitis].. https://pubmed.ncbi.nlm.nih.gov/5642259/
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Nonrandomized trials of postmenopausal estrogen replacement have shown a benefit in the prevention of coronary artery disease. Less clear are the specific mechanisms by which this occurs. Estrogen has beneficial effects on the lipid profile, with significant elevations in high density lipoprotein cholesterol and reductions in low density lipoprotein cholesterol reported. Also, antioxidant properties have been ascribed to estrogen. In addition, estrogen has been shown to prevent paradoxic vasoconstriction in atherosclerotic coronary arteries after acetylcholine and may have calcium channel-blocking and alpha2-inhibiting properties. Other proposed mechanisms of cardiovascular protection include reductions in serum fibrinogen and increases in prostacyclin biosynthesis. There is some evidence that cardiovascular biomechanics may be mildly depressed after menopause and that estrogen may normalize these changes by increasing ventricular contractility and, possibly, relaxation. Far less is known about the cardiovascular effects of progesterone, but overall it does not appear that the less androgenic progestins substantially modify the effects of estrogen. Because more women > 50 years old die of cardiovascular disease than any other cause, further clinical investigations of the risks and benefits of estrogen replacement and combined estrogen and progesterone therapy are clearly needed.
Protein C inhibitor (PCI) inhibits multiple plasma serine proteases. To determine which residues contribute to its specificity of inhibition, 19 mutations in the reactive site loop of PCI (from Thr352 to Arg357) were generated and assayed with thrombin, activated protein C (APC), and factor Xa. To identify the intermolecular interactions responsible for these kinetics, a molecular model of PCI was generated using alpha 1-protease inhibitor and ovalbumin as templates. This model of PCI was docked with thrombin, followed by extensive energy minimization, to determine a lowest energy complex. The resulting docked complex was used as a template to form molecular models of PCI-APC and PCI-factor Xa complexes. The best inhibitors of thrombin contained Pro or Gly at the P2 position in place of Phe353, with 2- and 7-fold increases in activity, respectively. These substitutions reduced steric interactions with the 60-insertion loop unique to thrombin. The best inhibitors of APC and factor Xa contained Arg at the P3 position in place of Thr352, with 2- and 5-fold increases in inhibition rates, respectively. The molecular model predicts that Arg in this position could form a salt bridge with Glu217 of each protease. Changing Arg357 at the P3' position had little effect on protease inhibition, consistent with the observation in the model that this residue points toward the body of PCI, forming a salt bridge with Glu220. Given its broad specificity of inhibition, PCI has proven very useful in understanding the nature of serpin-protease interactions using multiple mutations in a serpin assayed with multiple proteases.
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