+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



Faseb Journal 18(7): 828-835



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 hKLK1 counteracts the progression of LV contractile dysfunction and extracellular matrix remodeling in STZ-induced diabetic cardiomyopathy via a BK B2 receptor-dependent pathway.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 009946654

Download citation: RISBibTeXText

PMID: 15117887

DOI: 10.1096/fj.03-0736com


Related references

Transgenic activation of the kallikrein-kinin system prevents streptozotocin-diabetic hearts from cardiac fibrosis and left ventricular dysfunction. European Heart Journal 22(Abstract Supplement): 54, September, 2001

Transgenic expression of human kallikrein prevents altered left ventricular function, the decline in sarcoplasmic reticulum calcium pump activity and the rise in cardiac collagen content in diabetic rats. Circulation 102(18 Supplement): II 267, October 31, 2000

Transgenic expression of kallikrein prevents left ventricular dysfunction and inhibits endothelial induction of ICAM-1 and intramyocardial LFA-1/Mac-1+ infiltration in streptozotocin-induced diabetic cardiopathy in rats. Circulation 104(17 Supplement): II 198, October 23, 2001

Cardiac-specific IGF-1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy. Diabetes 59(6): 1512-1520, 2010

Prevention of sarcoplasmic reticular Ca transport dysfunction in diabetic heart with transgenic human kallikrein expression is not due to altered SERCA2 and phospholamban expression. Naunyn-Schmiedeberg's Archives of Pharmacology 362(4-5 Supplement): R29, 2000

Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms. Circulation 119(10): 1398-1407, 2009

Preserved cardiac function during diabetes mellitus in transgenic rats expressing the human tissue kallikrein gene. Circulation 100(18 SUPPL ): I 117, Nov 2, 1999

Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. Faseb Journal 14(13): 1858-1860, 2000

Human tissue kallikrein gene delivery attenuates cardiac glycogen accumulation in streptozotocin-induced diabetic rats. Hypertension (Baltimore) 36(4): 703, October, 2000

Fluvastatin attenuates myocardial interstitial fibrosis and cardiac dysfunction in diabetic rats by inhibiting over-expression of connective tissue growth factor. Chinese Medical Journal 124(1): 89-94, 2011

Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction. Proceedings of the National Academy of Sciences of the United States of America 99(24): 15333-8, 2002

Transgenic activation of the kallikrein-kinin system reduces intramyocardial expression of TNFa and II-1b and improves left ventricular function in experimental diabetic cardiopathy. European Heart Journal 22(Abstract Supplement): 680, September, 2001

Transgenic expression of human kallikrein prevents sarcoplasmic reticular calcium ion transport dysfunction in diabetic rat heart. Hypertension (Baltimore) 36(4): 655, October, 2000

Survivin gene therapy attenuates left ventricular systolic dysfunction in doxorubicin cardiomyopathy by reducing apoptosis and fibrosis. Cardiovascular Research 101(3): 423-433, 2014