Effects of Hyperfibrinogenemia on Vasculature of C57BL/6 Mice With and Without Atherogenic Diet

Abstract

Objective-Elevated fibrinogen is correlated with severe atherosclerosis, as defined by the occurrence of ischemic events, but the mechanistic basis for this correlation remains unknown. To study this relationship, we examined spontaneous and diet-induced atherosclerosis in transgenic mice with hyperfibrinogenemia (elevated fibrinogen). Methods and Results-Normal and transgenic mice were fed either an atherogenic diet or simple breeder chow. We measured plasma fibrinogen levels and identified an age-dependent and diet-dependent increase in fibrinogen. After 8 to 12 months, aortic sections were prepared and stained, and lipid-containing lesions were counted, measured, and assessed for maturity. Lipid-filled deposits appeared spontaneously in a small number of mice on breeder chow; typical fatty streak-type lesions appeared in almost all of the diet-fed animals. Morphometric analysis showed that neither the number nor the size of lesions was influenced by either fibrinogen level or genotype. Conclusions-Our data showed that neither fibrinogen concentration nor genotype had a statistically significant effect on the initiation, initial growth, or early progression of atherosclerotic lesions.

Cause-effect relation between hyperfibrinogenemia and vascular disease

“…The added transgenic fibrinogen allele is inherited in a Mendelian fashion, and the mice were reported to exhibit approximately 2-fold augmented plasma fibrinogen levels yet were free from overt signs of disease and displayed normal reproductive performance. 18 Transgene-dependent hyperfibrinogenemia had no effect on diet-induced atherogenesis in C57Bl6 mice 19 or in ApoE*3-Leiden transgenic mice. 20 The objective of the current study was to investigate whether chronically elevated fibrinogen in Hifib mice (1) causes increased intravascular fibrin deposition or altered fibrin(ogen) turnover; (2) modifies platelet-thrombus formation in response to acute endothelial injury; (3) affects the incidence or extent of stasis-induced thrombosis and vascular remodeling; or (4) augments thrombosis in mice with an underlying hypercoagulable state.…”

A reconstituted HDL containing V156K or R173C apoA-I exhibited anti-inflammatory activity in apo-E deficient mice and showed resistance to myeloperoxidase-mediated oxidation

“…Aortic lesion formation was assessed using the method described by Paigen et al (1987) with slight modification (Gulledge et al, 2003). Briefly, after the mice were bled to death, their hearts were perfused via the left ventricle with 30 ml of 4% paraformaldehyde, and then fixed for at least 24 h. The isolated upper heart/aortic sinus was then embedded in Tissue-Tek OCT compound (Fisher Scientific, Pittsburgh, PA) and frozen.…”

A point mutant of apolipoprotein A-I, V156K, exhibited potent anti-oxidant and anti-atherosclerotic activity in hypercholesterolemic C57BL/6 mice

“…Aortic lesion formation was evaluated via a previously described method (Paigen et al, 1987) with the slight modifications described by Gulledge et al (2003). After the mice were exsanguinated, their hearts were perfused through the left ventricle with 30 ml of 4% paraformaldehyde and fixed for at least 24 h. The isolated upper heart/aortic sinus was then embedded in Tissue-Tek OCT compound (Fisher Scientific, Pittsburgh, PA), and frozen.…”