title: Cardiac kallikrein-kinin system is upregulated in chronic volume overload and mediates an inflammatory induced collagen loss.
abstract: BACKGROUND
  The clinical problem of a "pure volume overload" as in isolated mitral or aortic regurgitation currently has no documented medical therapy that attenuates collagen loss and the resultant left ventricular (LV) dilatation and failure. Here, we identify a potential mechanism related to upregulation of the kallikrein-kinin system in the volume overload of aortocaval fistula (ACF) in the rat.
  
  
  RESULTS
  LV interstitial fluid (ISF) collection, hemodynamics, and echocardiography were performed in age-matched shams and 4 and 15 wk ACF rats. ACF rats had LV dilatation and a 2-fold increase in LV end-diastolic pressure, along with increases in LV ISF bradykinin, myocardial kallikrein and bradykinin type-2 receptor (BK(2)R) mRNA expression. Mast cell numbers were increased and interstitial collagen was decreased at 4 and 15 wk ACF, despite increases in LV ACE and chymase activities. Treatment with the kallikrein inhibitor aprotinin preserved interstitial collagen, prevented the increase in mast cells, and improved LV systolic function at 4 wk ACF. To establish a cause and effect between ISF bradykinin and mast cell-mediated collagen loss, direct LV interstitial bradykinin infusion in vivo for 24 hrs produced a 2-fold increase in mast cell numbers and a 30% decrease in interstitial collagen, which were prevented by BK(2)R antagonist. To further connect myocardial stretch with cellular kallikrein-kinin system upregulation, 24 hrs cyclic stretch of adult cardiomyocytes and fibroblasts produced increased kallikrein, BK(2)R mRNA expressions, bradykinin protein and gelatinase activity, which were all decreased by the kallikrein inhibitor-aprotinin.
  
  
  CONCLUSIONS
  A pure volume overload is associated with upregulation of the kallikrein-kinin system and ISF bradykinin, which mediates mast cell infiltration, extracellular matrix loss, and LV dysfunction-all of which are improved by kallikrein inhibition. The current investigation provides important new insights into future potential medical therapies for the volume overload of aortic and mitral regurgitation.
authors: Birmingham Veteran Affairs Medical Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. chih@uab.edu
authors: Chih-Chang
authors: CC
authors: Wei
authors: Yuanwen
authors: Y
authors: Chen
authors: Lindsay C
authors: LC
authors: Powell
authors: Junying
authors: J
authors: Zheng
authors: Ke
authors: K
authors: Shi
authors: Wayne E
authors: WE
authors: Bradley
authors: Pamela C
authors: PC
authors: Powell
authors: Sarfaraz
authors: S
authors: Ahmad
authors: Carlos M
authors: CM
authors: Ferrario
authors: Louis J
authors: LJ
authors: Dell'Italia
mesh_terms: D000804:Angiotensin II / Q000097:blood; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D001920:Bradykinin / Q000097:blood; D002395:Catecholamines / Q000097:blood; D002452:Cell Count; D015550:Cell Degranulation / Q000187:drug effects; D053818:Chymases / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D045604:Extracellular Fluid; D018093:Gelatinases / Q000378:metabolism; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000473:pathology*; D016234:Kallikrein-Kinin System / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018002:Receptors, Bradykinin / Q000378:metabolism; D014463:Ultrasonography; D015854:Up-Regulation / Q000187:drug effects; D016157:Vascular Fistula / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D002395:Catecholamines; D012333:RNA, Messenger; D018002:Receptors, Bradykinin; D000804:Angiotensin II; D003094:Collagen; D007611:Aprotinin; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D053818:Chymases; D018093:Gelatinases; D001920:Bradykinin