TY - JOUR
T1 - PGC-1β deficiency accelerates the transition to heart failure in pressure overload hypertrophy
AU - Riehle, Christian
AU - Wende, Adam R.
AU - Zaha, Vlad G.
AU - Pires, Karla Maria
AU - Wayment, Benjamin
AU - Olsen, Curtis
AU - Bugger, Heiko
AU - Buchanan, Jonathan
AU - Wang, Xiaohui
AU - Moreira, Annie Bello
AU - Doenst, Torsten
AU - Medina-Gomez, Gema
AU - Litwin, Sheldon E.
AU - Lelliott, Christopher J.
AU - Vidal-Puig, Antonio
AU - Abel, E. Dale
PY - 2011/9/16
Y1 - 2011/9/16
N2 - Rationale: Pressure overload cardiac hypertrophy, a risk factor for heart failure, is associated with reduced mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) proteins that correlate in rodents with reduced PGC-1α expression. Objective: To determine the role of PGC-1β in maintaining mitochondrial energy metabolism and contractile function in pressure overload hypertrophy. Methods and Results: PGC-1β deficient (KO) mice and wildtype (WT) controls were subjected to transverse aortic constriction (TAC). Although LV function was modestly reduced in young KO hearts, there was no further decline with age so that LV function was similar between KO and WT when TAC was performed. WT-TAC mice developed relatively compensated LVH, despite reduced mitochondrial function and repression of OXPHOS and FAO genes. In nonstressed KO hearts, OXPHOS gene expression and palmitoyl-carnitine- supported mitochondrial function were reduced to the same extent as banded WT, but FAO gene expression was normal. Following TAC, KO mice progressed more rapidly to heart failure and developed more severe mitochondrial dysfunction, despite a similar overall pattern of repression of OXPHOS and FAO genes as WT-TAC. However, in relation to WT-TAC, PGC-1β deficient mice exhibited greater degrees of oxidative stress, decreased cardiac efficiency, lower rates of glucose metabolism, and repression of hexokinase II protein. Conclusions: PGC-1β plays an important role in maintaining baseline mitochondrial function and cardiac contractile function following pressure overload hypertrophy by preserving glucose metabolism and preventing oxidative stress.
AB - Rationale: Pressure overload cardiac hypertrophy, a risk factor for heart failure, is associated with reduced mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) proteins that correlate in rodents with reduced PGC-1α expression. Objective: To determine the role of PGC-1β in maintaining mitochondrial energy metabolism and contractile function in pressure overload hypertrophy. Methods and Results: PGC-1β deficient (KO) mice and wildtype (WT) controls were subjected to transverse aortic constriction (TAC). Although LV function was modestly reduced in young KO hearts, there was no further decline with age so that LV function was similar between KO and WT when TAC was performed. WT-TAC mice developed relatively compensated LVH, despite reduced mitochondrial function and repression of OXPHOS and FAO genes. In nonstressed KO hearts, OXPHOS gene expression and palmitoyl-carnitine- supported mitochondrial function were reduced to the same extent as banded WT, but FAO gene expression was normal. Following TAC, KO mice progressed more rapidly to heart failure and developed more severe mitochondrial dysfunction, despite a similar overall pattern of repression of OXPHOS and FAO genes as WT-TAC. However, in relation to WT-TAC, PGC-1β deficient mice exhibited greater degrees of oxidative stress, decreased cardiac efficiency, lower rates of glucose metabolism, and repression of hexokinase II protein. Conclusions: PGC-1β plays an important role in maintaining baseline mitochondrial function and cardiac contractile function following pressure overload hypertrophy by preserving glucose metabolism and preventing oxidative stress.
KW - cardiac hypertrophy
KW - gene expression
KW - heart failure
KW - mitochondria
UR - http://www.scopus.com/inward/record.url?scp=80052970004&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052970004&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.111.243964
DO - 10.1161/CIRCRESAHA.111.243964
M3 - Article
C2 - 21799152
AN - SCOPUS:80052970004
SN - 0009-7330
VL - 109
SP - 783
EP - 793
JO - Circulation research
JF - Circulation research
IS - 7
ER -