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

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Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene.
Authors:	Tschope, C Walther, T Koniger, J Spillmann, F Westermann, D Escher, F Pauschinger, M Pesquero, JB Bader, M Schultheiss, HP Noutsias, M
Citation:	Tschope C, etal., FASEB J. 2004 May;18(7):828-35.
RGD ID:	1641802
Pubmed:	PMID:15117887 (View Abstract at PubMed)
DOI:	DOI:10.1096/fj.03-0736com (Journal Full-text)
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.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
KLK1	Human	cardiomyopathy		IDA		associated with Diabetes Mellitus and Experimental	RGD
Klk1c12	Rat	cardiomyopathy		ISO	KLK1 (Homo sapiens)	associated with Diabetes Mellitus and Experimental	RGD

Objects Annotated

Genes (Rattus norvegicus)

Klk1c12 (kallikrein 1-related peptidase C12)

Genes (Homo sapiens)

KLK1 (kallikrein 1)

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