title: Dynamic molecular and histopathological changes in the extracellular matrix and inflammation in the transition to heart failure in isolated volume overload.
abstract: Left ventricular (LV) volume overload (VO) causes eccentric remodeling with inflammatory cell infiltration and extracellular matrix (ECM) degradation, for which there is currently no proven therapy. To uncover new pathways that connect inflammation and ECM homeostasis with cellular dysfunction, we determined the cardiac transciptome in subacute, compensated, and decompensated stages based on in vivo hemodynamics and echocardiography in the rat with aortocaval fistula (ACF). LV dilatation at 5 wk was associated with a normal LV end-diastolic dimension-to-posterior wall thickness ratio (LVEDD/PWT; compensated), whereas the early 2-wk (subacute) and late 15-wk (decompensated) ACF groups had significant increases in LVEDD/PWT. Subacute and decompensated stages had a significant upregulation of genes related to inflammation, the ECM, the cell cycle, and apoptosis. These changes were accompanied by neutrophil and macrophage infiltration, nonmyocyte apoptosis, and interstitial collagen loss. At 15 wk, there was a 40-fold increase in the matricellular protein periostin, which inhibits connections between collagen and cells, thereby potentially mediating a side-to-side slippage of cardiomyocytes and LV dilatation. The majority of downregulated genes was composed of mitochondrial enzymes whose suppression progressed from 5 to 15 wk concomitant with LV dilatation and systolic heart failure. The profound decrease in gene expression related to fatty acid, amino acid, and glucose metabolism was associated with the downregulation of peroxisome proliferator associated receptor (PPAR)-α-related and bioenergetic-related genes at 15 wk. In VO, an early phase of inflammation subsides at 5 wk but reappears at 15 wk with marked periostin production along with the suppression of genes related to PPAR-α and energy metabolism.
authors.affiliation: Center for Heart Failure Research, Division of Cardiology, Univ. of Alabama at Birmingham, 434 BMR2, 1530 3rd Ave. S., Birmingham, AL 35294-2180, USA.
authors.forename: Yuan-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Betty
authors.initials: B
authors.lastname: Pat
authors.forename: James D
authors.initials: JD
authors.lastname: Gladden
authors.forename: Junying
authors.initials: J
authors.lastname: Zheng
authors.forename: Pamela
authors.initials: P
authors.lastname: Powell
authors.forename: Chih-Chang
authors.initials: CC
authors.lastname: Wei
authors.forename: Xiangqin
authors.initials: X
authors.lastname: Cui
authors.forename: Ahsan
authors.initials: A
authors.lastname: Husain
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'italia
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018450:Disease Progression; D004734:Energy Metabolism / Q000502:physiology; D005109:Extracellular Matrix / Q000473:pathology*; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D007249:Inflammation / Q000473:pathology*; D008297:Male; D023421:Models, Animal; D047493:PPAR alpha / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D015815:Cell Adhesion Molecules; D047493:PPAR alpha; C512836:Postn protein, rat