Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene

ABSTRACT Diabetic cardiomyopathy includes fibrosis. Kallikrein (KLK) can inhibit collagen synthesis and promote collagen breakdown. We investigated cardiac fibrosis and left ventricular (LV) function in transgenic rats (TGR) expressing the human kallikrein 1 (hKLK1) gene in streptozotocin (STZ) ‐induced diabetic conditions. Six weeks after STZ injection, LV function was determined in male Sprague‐Dawley (SD) rats and TGR(hKLK1) ( n =10/group) by a Millar tip catheter. Total collagen content (Sirius Red staining) and expression of types I, III, and VI collagen were quantified by digital image analysis. SD‐STZ hearts demonstrated significantly higher total collagen amounts than normoglycemic controls, reflected by the concomitant increment of collagen types I, III, and VI. This correlated with a significant reduction of LV function vs. normoglycemic controls. In contrast, surface‐specific content of the extracellular matrix, including collagen types I, III, and VI expression, was significantly lower in TGR(hKLK1)‐STZ, not exceeding the content of SD and TGR(hKLK1) controls. This was paralleled by a preserved LV function in TGR(hKLK1)‐STZ animals. The kallikrein inhibitor aprotinin and the bradykinin (BK) B2 receptor antagonist icatibant reduced the beneficial effects on LV function and collagen content in TGR(hKLK1)‐STZ animals. Transgenic expression of hKLKl counteracts the progression of LV contractile dysfunction and extracellular matrix remodeling in STZ‐induced diabetic cardiomyopathy via a BK B2 receptor‐dependent pathway.—Tschope, C., Walther, T., Königer, J., Spillmann, F., Westermann, D., Escher, F., Pauschinger, M., Pesquero, J. B., Bader, M., Schultheiss, H.‐P., Noutsias, M. Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. FASEB J. 18, 828–835 (2004)