Regional distribution of mitochondrial dysfunction and apoptotic remodeling in pacing-induced heart failure.
BACKGROUND
Specific myocardial mitochondrial enzymatic dysfunction and apoptotic remodeling occur in pacing-induced heart failure. We sought to define their regional distribution and molecular basis in the failing heart.


RESULTS
Enzyme dysfunction was assessed in mitochondrial subpopulations and immunoblot analysis was performed using homogenate proteins from the left atria (LA) and left ventricle (LV) of paced and control mongrel dogs. A greater range of enzymatic defects (complex I, III, and V) was found in mitochondria subpopulations from the LV as compared with the LA (where only complex V was defective). Analysis of paced LV proteins demonstrated a downregulated expression of both mitochondrial genes (eg, cytochrome b) and nuclear genes (eg, ATP synthase beta subunit, mitochondrial creatine kinase). Protease-activated products of both mitochondrial (eg, apoptosis inducing factor) and cytosolic (eg, caspase-3) apoptogenic proteins were increased in both the LA and LV. Nuclear-localized apoptotic markers (eg, p53, p21) were also significantly increased in the LV of paced dogs.


CONCLUSIONS
Abnormal activity of several mitochondrial enzymes and increased apoptogenic pathway appear to be mediated, at least in part, by an orchestrated shift in expression (both nuclear and mitochondrial DNA) of respiratory chain subunits (eg, cyt b, ATP-beta), mitochondrial bioenergetic enzymes (eg, mitochondrial creatine kinase), global transcription factor (eg, PGC-1), and apoptotic proteins (eg, p53, p21) with distinct differences in their regional distribution and in the subpopulations of mitochondria affected.
Molecular Cardiology and Neuromuscular Institute, Highland Park, NJ 08904, USA. tmci@att.net
José
J
Marín-García
Michael J
MJ
Goldenthal
Shirish
S
Damle
Yeqing
Y
Pi
Gordon W
GW
Moe
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects*; D004195:Disease Models, Animal; D004285:Dogs; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*