Abstract 15331: Reduced Fibulin-4 Expression Induces Cardiomyocyte Remodeling and Dilated Cardiomyopathy
Fibulin-4 is a glycoprotein, expressed in medial layers of arteries, heart valves and the myocardium. Mice homozygous for the fibulin-4 reduced expression allele (Fibulin-4R/R) show severe dilation of the ascending aorta resulting from disorganized elastic fibers and excessive TGFβ signaling. Strikingly, even a modest reduction in the Fibulin-4+/R mice results in mild abnormalities. We used these mice to determine whether fibulin-4 is associated with primary cardiomyopathy and to identify changes in protein expression patterns underlying the cardiovascular abnormalities. Echocardiography demonstrated poor aortic valve function, resulting in severe dilated cardiomyopathy in Fibulin-4R/R mice. In Fibulin-4+/R mice, only mild deterioration of cardiac function was observed, in the absence of aortic valve disease. Functionally, this resulted in a gradual reduction in ejection fraction from 70% in Fibulin-4+/+ to 57% in Fibulin-4+/R and 17% in Fibulin-4R/R mice (p for trend <0.0001). Furthermore, cardiomyocyte area increased gene-dose dependently, but only in Fibulin-4R/R mice this was associated with LV remodeling and higher BNP levels. A full un-biased qualitative MS/MS proteomic screen of the aorta protein extracts of fibulin-4 mice identified an increase in mitochondrial oxidative phosphorylation as the major deregulated pathway. Next, an overlay of the aortic proteome and transcriptome resulted in a limited set of biomarkers. In the Fibulin-4R/R mice this pointed towards the inflammation associated TNFα pathway and an altered regulation of 17β-estradiol. Interestingly, the latter was also found in the Fibulin-4+/R mice. This signaling molecule is a metabolite known to deregulate production of reactive oxygen species (ROS) by poorly understood mechanisms. Notably, both mitochondrial function and the 17β-estradiol pathway are deregulated by oxidative stress, which is a hallmark of aging and age-related cardiovascular diseases. Increased arterial aging was subsequently evidenced by a gradual increase in ROS production, endothelial dysfunction and aortic stiffness in fibulin-4 mutant mice. These results uncover new regulatory pathways likely to be associated with enhanced cardiovascular aging in aneurysmal fibulin-4 mice.
- © 2011 by American Heart Association, Inc.