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

Abstract

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 Ca(2+)-induced MPT, which was completely normalized by treatment with DHA and partially corrected by EPA. In conclusion, treatment with DHA or EPA normalizes Ca(2+)-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.

Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies

“…␦-Sarcoglycan null hamsters, a rodent model of dilated cardiomyopathy that exhibits decreased mitochondrial oxidative capacity and is responsive to nutritional and metabolic therapies, displayed distinct effects to the IFM subpopulation. These effects included a decrease in mitochondrial yield and direct impact on Ca 2ϩ -induced mPTP (37,38). These data are in agreement with others using cardiomyopathic hamsters in a time course analyses in which defective oxidative phosphorylation was confined to the IFM subpopulation.…”

Enhanced resistance to permeability transition in interfibrillar cardiac mitochondria in dogs: effects of aging and long-term aldosterone infusion

“…Furthermore, studies in rat heart found that IFM are more resistant to stress-induced MPT than SSM, as reflected in greater Ca 2ϩ retention capacity and Ca 2ϩ -induced release of cytochrome c (15,20,35). This is not a consistent finding, as we found similar Ca 2ϩ retention capacities in IFM and SSM in mitochondria from healthy hamsters and in normal rats or rats with infarct-induced heart failure (8,9,30). In contrast to those of rats and healthy hamsters, IFM from cardiomyopathic hamsters have lower respiration rates and a greater susceptibility to Ca 2ϩ -induced MPT than SSM (8,16).…”

EPA, not DHA, prevents fibrosis in pressure overload-induced heart failure: potential role of free fatty acid receptor 4

“…DHA has known effects in the TAC model, including inhibition of mitochondrial transition pore opening ( 45,46 ), but whether this improves survival is not clear ( 45 ). Our data suggest that EPA-mediated prevention of fi brosis does not completely reverse diastolic dysfunction ( Fig.…”