Marine n3 polyunsaturated fatty acids enhance resistance to mitochondrial permeability transition in heart failure but do not improve survival

Mitochondrial dysfunction in heart failure includes greater susceptibility to mitochondrial permeability transition (MPT), which may worsen cardiac function and decrease survival. Treatment with a mixture of the n3 polyunsaturated fatty acids (n3 PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial in heart failure patients and increases resistance to MPT in animal models. We assessed whether DHA and EPA have similar effects when given individually, and whether they prolong survival in heart failure. Male δ-sarcoglycan null cardiomyopathic hamsters were untreated or given either DHA, EPA, or a 1:1 mixture of DHA + EPA at 2.1% of energy intake. Treatment did not prolong survival: mean survival was 298 ± 15 days in untreated hamsters and 335 ± 17, 328 ± 14, and 311 ± 15 days with DHA, EPA, and DHA + EPA, respectively ( n = 27–32/group). A subgroup of cardiomyopathic hamsters treated for 26 wk had impaired left ventricular function and increased cardiomyocyte apoptosis compared with normal hamsters, which was unaffected by n3 PUFA treatment. Evaluation of oxidative phosphorylation in isolated subsarcolemmal and interfibrillar mitochondria with substrates for complex I or II showed no effect of n3 PUFA treatment. On the other hand, interfibrillar mitochondria from cardiomyopathic hamsters were significantly more sensitive to Ca2+-induced MPT, which was completely normalized by treatment with DHA and partially corrected by EPA. In conclusion, treatment with DHA or EPA normalizes Ca2+-induced MPT in cardiomyopathic hamsters but does not prolong survival or improve cardiac function. This suggest that greater susceptibility to MPT is not a contributor to cardiac pathology and poor survival in heart failure.

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Cyclosporine A attenuates mitochondrial permeability transition and improves mitochondrial respiratory function in cardiomyocytes isolated from dogs with heart failure

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2006.09.013 ◽

2007 ◽

Vol 42 (1) ◽

pp. 150-158 ◽

Cited By ~ 70

Author(s):

Victor G. Sharov ◽

Anastassia Todor ◽

Sanjaya Khanal ◽

Makoto Imai ◽

Hani N. Sabbah

Keyword(s):

Heart Failure ◽

Cyclosporine A ◽

Respiratory Function ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Mitochondrial Permeability ◽

Mitochondrial Respiratory

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Abstract 16743: A Kinase Interacting Protein 1 Does Not Protect From Adverse Cardiac Remodelling but Attenuates Myocardial Ischemia - Reperfusion Injury

Circulation ◽

10.1161/circ.132.suppl_3.16743 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Harmen G Booij ◽

Hongjuan Yu ◽

Rudolf A de Boer ◽

Wiek H van Gilst ◽

Herman H Silljé ◽

...

Keyword(s):

Heart Failure ◽

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Ischemia Reperfusion ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Wild Type ◽

Interacting Protein ◽

Mitochondrial Permeability ◽

Myocardial Ischemia Reperfusion

Introduction: A kinase interacting protein 1 (AKIP1) attenuates myocardial ischemia / reperfusion (I/R) injury and stimulates beneficial cardiac remodeling in cultured cardiomyocytes. Whether these findings translate into functional benefits in vivo remains to be established. Hypothesis: We assessed the hypothesis that cardiac overexpression of AKIP1 attenuates myocardial heart failure development or I/R-injury in mice. Methods: We created transgenic mice with cardiac-specific overexpression of AKIP1 (AKIP1-TG). First, AKIP1-TG mice or their wild type littermates were subjected to transverse aortic constriction (TAC) and myocardial infarction (MI) with permanent ligation of the left coronary artery. Second, infarct size after 45 minutes ischemia followed by 24h reperfusion was assessed with Evans Bleu and triphenyltetrazolium chloride staining. Results: AKIP1-TG mice and wild type littermates displayed similar left ventricular remodeling and function after TAC or MI as measured with magnetic resonance imaging. Histological indices of heart failure severity, including cardiomyocyte cross-sectional area, capillary density and fibrosis were also similar. However, infarct size relative to the area at risk was reduced 2-fold in AKIP1-TG mice after I/R (15% ± 3 vs. 29± 4 %, p<0,05) and accompanied with a marked reduction in apoptosis (5,4 ± 0,5% vs. 8,1 ± 1,1%, p<0,05). AKIP1 overexpression did not influence cardiac transcription or signaling. Subcellular fraction studies showed enrichment of AKIP1 in mitochondria. In addition, AKIP1 attenuated calcium induced swelling of mitochondria (0.77 ± 0.01 vs. 0.71 ± 0.01, p<0.05), suggesting a direct role for AKIP1 in the mitochondrial permeability transition pore. Conclusions: In conclusion, AKIP1 does not influence cardiac remodeling in models of chronic heart failure. However, AKIP1 does attenuate myocardial I/R injury through stabilization of the mitochondrial permeability transition pore.

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