title: Novel mechanism of plasma prekallikrein (PK) activation by vascular smooth muscle cells: evidence of the presence of PK activator.
abstract: The contribution of plasma prekallikrein (PK) to vascular remodeling is becoming increasingly recognized. Plasma PK is activated when the zymogen PK is digested to an active enzyme by activated factor XII (FXII). Here, we present our findings that vascular smooth muscle cells (VSMC) activate plasma PK in the absence of FXII. Extracted plasma membrane and cytosolic fractions of VSMCs activate PK, but the rate of PK activation was greater by the membrane fraction. FXII neutralizing antibody did not affect PK activation by extracted proteins of VSMCs. VSMC PKA was inhibited by the serine protease inhibitors such as aprotinin, phenylmethylsulfonyl fluoride, leupeptin and CTI with CI50 of 0.78 μM, 1 mM, 3.13 μM and 40 nM on the cultured cells, respectively. No inhibition of PK activation by cysteine, aspartic acid, and metalloprotease inhibitors was observed. This is the first report of the presence of an intrinsic PKA in VSMC. Considering that VSMCs are normally separated from the circulating blood by endothelial cells, direct PK activation by VSMCs may play a role in disease states like diabetes, hyperlipidemia or hypertension where the endothelial layer is damaged.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Keum
authors.affiliation: Epidemiology and Population Health Department, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon.
authors.forename: M A
authors.initials: MA
authors.lastname: Jaffa
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Luttrell
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Jaffa
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D011288:Prekallikrein / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011480:Protease Inhibitors; D000804:Angiotensin II; D011288:Prekallikrein; D001920:Bradykinin