Loss of interstitial collagen causes structural and functional alterations of cardiomyocyte subsarcolemmal mitochondria in acute volume overload.
Volume overload (VO) caused by aortocaval fistula (ACF) is associated with oxidative/inflammatory stress. The resulting inflammation, matrix metalloproteinase (MMP) activation, and collagen degradation is thought to play a pivotal role in left ventricular (LV) dilatation and failure. Since mitochondria are also targets for inflammation and oxidative stress, we hypothesized that there would be bioenergetic dysfunction with acute VO. In Sprague-Dawley rats subjected to 24 hrs of ACF, there was a two-fold increase in LV pressure-volume area in vivo, consistent with increased LV myocardial oxygen usage and increased bioenergetic demand in cardiomyocytes. Isolated cardiomyocytes from ACF LVs demonstrated increased hydrogen peroxide and superoxide formation and increased MMP activity. Subsarcolemmal mitochondria (SSM) showed a 40% decrease in state 3 respiration and proteomic analysis of SSM demonstrated decreased levels of complexes I-V in ACF. Immunohistochemical analysis revealed disruption of the subsarcolemmal location of the SSM network in ACF. To test for a potential link between SSM dysfunction and loss of interstitial collagen, rats were treated with the MMP-inhibitor PD166793 prior to ACF. MMP-inhibitor preserved interstitial collagen, integrin-α5 and the SSM structural arrangement. In addition, the decrease in state 3 mitochondrial respiration with ACF was prevented by PD166793. These studies established an important interaction between degradation of interstitial collagen in acute VO and the disruption of SSM structure and function which could contribute to progression to heart failure.
UAB Center for Heart Failure Research, University of Alabama at Birmingham, Birmingham, AL 35294-2180, USA.
Elena
E
Ulasova
James D
JD
Gladden
Yuanwen
Y
Chen
Junying
J
Zheng
Betty
B
Pat
Wayne
W
Bradley
Pamela
P
Powell
Jaroslaw W
JW
Zmijewski
Blake R
BR
Zelickson
Scott W
SW
Ballinger
Victor
V
Darley-Usmar
Louis J
LJ
Dell'italia
D000818:Animals; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism*; D004453:Echoencephalography; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000502:physiology
D003094:Collagen