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Dysfunctional mitochondria (MITO) and cardiomyocyte apoptosis occur in heart failure (HF). Bendavia (MTP-131), a first-in-class MITO protective agent, improves LV function and ATP synthesis in HF dogs. We examined the effects of Bendavia on protein level and activity of cytochrome-c oxidase complex IV (COXIV), a contributor to MITO ATP synthesis, and on protein level of cytosolic cytochrome-c (CCC), a mediator of apoptosis, in LV of dogs with microembolization-induced HF (LV ejection fraction ∼30%).
12 HF dogs were randomized to 3 months therapy with subcutaneous injections of Bendavia (0.5 mg/kg once daily, n=7) or saline (Control, n=7). LV tissue obtained at end of therapy and from 6 normal (NL) dogs was used to measure COXIV activity polarographically and protein level of COXIV, CCC and β-actin, an internal control, by Western blotting in homogenate and cytosolic fraction.
β-actin level was unchanged among groups. COXIV activity and protein level were reduced and CCC protein level was increased in HF Controls compared to NL (Table). Bendavia increased the activity and protein level of COXIV and decreased protein level of CCC to near NL (Table).
Downregulation of COXIV activity and expression and upregulation of CCC protein level in LV of HF dogs favor a state of energy deprivation and enhanced apoptosis. Bendavia restores regulation of COXIV and CCC to near normal levels; a correction that favors improved myocardial energetics and reduced apoptosis in HF.
|COXIV Activity (nmols molecular oxygen/min/mg protein)||7506 ± 282||4220 ± 240*||6509 ± 443†|
|β-actin in homogenate (du)||0.44 ± 0.51||0.41 ± 0.04||0.45 ± 0.06|
|β-actin in cytosol (du)||0.33 ± 0.06||0.31 ± 0.06||0.37 ± 0.06|
|COXIV protein (du)||0.61 ± 0.05||0.18 ± 0.02*||0.40 ± 0.06t|
|CCC protein (du)||0.34 ± 0.02||0.75 ± 0.08*||0.39 ± 0.02t|
Poster Sessions, Expo North
Sunday, March 10, 2013, 9:45 a.m.-10:30 a.m.
Session Title: Heart Failure: Pharmacologic Therapy
Abstract Category: 17. Heart Failure: Therapy
Presentation Number: 1223-311
- 2013 American College of Cardiology Foundation