Cardiac function and remodeling is attenuated in transgenic rats expressing the human kallikrein-1 gene after myocardial infarction.
Bradykinin coronary outflow, left ventricular performance and left ventricular dimensions of transgenic rats harboring the human tissue kallikrein-1 gene TGR(hKLK1) were investigated under basal and ischemic conditions. Bradykinin content in the coronary outflow of buffer-perfused, isolated hearts of controls and TGR(hKLK1) was measured by specific radioimmunoassay before and after global ischemia. Left ventricular function and left ventricular dimensions were determined in vivo using a tip catheter and echocardiography 6 days and 3 weeks after induction of myocardial infarction. Left ventricular type I collagen mRNA expression was analyzed by RNase protection assay. Compared to controls, basal bradykinin outflow was 3.5 fold increased in TGR(hKLK1). Ischemia induced an increase of bradykinin coronary outflow in controls but did not induce a further increase in TGR(hKLK1). However, despite similar unchanged infarction sizes, left ventricular function and remodeling improved in TGR(hKLK1) after myocardial infarction, indicated by an increase in left ventricular pressure (+34%; P<0.05), contractility (dp/dt max. +25%; P<0.05), and in ejection fraction (+20%; P<0.05) as well as by a reduction in left ventricular enddiastolic pressure (-49%, P<0.05), left ventricular enddiastolic diameter (-20%, P<0.05), and collagen mRNA expression (-15%, P<0.05) compared to controls. A chronically activated transgenic kallikrein kinin system with expression of human kallikrein-1 gene counteracts the progression of left ventricular contractile dysfunction after experimental myocardial infarction. Further studies have to show whether these results can be caused by other therapeutically options. Long acting bradykinin receptor agonists might be an alternative option to improve ischemic heart disease.
Koch
Matthias
M
Department of Cardiology and Pneumology, Charité -- University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12220 Berlin, Germany.
Spillmann
Frank
F
Dendorfer
Andreas
A
Westermann
Dirk
D
Altmann
Christine
C
Sahabi
Merdad
M
Linthout
Sophie Van
SV
Bader
Michael
M
Walther
Thomas
T
Schultheiss
Heinz-Peter
HP
Tschöpe
Carsten
C
D000818:Animals; D030801:Animals, Genetically Modified; D001920:Bradykinin / Q000378:metabolism; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D023282:Nuclease Protection Assays; D051381:Rats; D017207:Rats, Sprague-Dawley; D020840:Tissue Kallikreins / Q000235:genetics*; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects*
D020840:Tissue Kallikreins; D001920:Bradykinin