Mitochondrial adaptations within chronically ischemic swine myocardium

McFalls, Edward O.; Sluiter, Willem; Schoonderwoerd, Kees; Manintveld, Olivier C.; Lamers, Jos M. J.; Bezstarosti, Karel; VANBEUSEKOM, H; Sikora, Joseph J.; Ward, Herbert B.; Merkus, Daphne

doi:10.1016/j.yjmcc.2006.07.008

Cited by 56 publications

(70 citation statements)

References 42 publications

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“…These data suggest that oyster mitochondria undergo minimal functional alterations during the prolonged "shutdown" in anoxic tissues, and the only significant functionally relevant change is a reduction in mitochondrial RCR. A similar moderate decrease in RCR without a concomitant decline in oxidation capacity was found in mammalian mitochondria during hypoxia/reoxygenation-resistant states induced by ischemic preconditioning or by pharmacological agents and was interpreted as a sign of mild uncoupling that serves as a protection mechanism against elevated ROS formation and associated mitochondrial and tissue damage (44,48,52). Possibly a similar mechanism is involved in mitochondrial protection during postanoxic recovery in oysters.…”

Section: Discussionsupporting

confidence: 56%

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Kurochkin

Ivanina

Eilers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Kurochkin IO, Ivanina AV, Eilers S, Downs CA, May LA, Sokolova IM. Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica). Am J Physiol Regul Integr Comp Physiol 297: R1262-R1272, 2009. First published September 2, 2009 doi:10.1152/ajpregu.00324.2009.-Benthic marine organisms such as mollusks are often exposed to periodic oxygen deficiency (due to the tidal exposure and/or seasonal expansion of the oxygen-deficient dead zones) and pollution by metals [e.g., cadmium, (Cd)]. These stressors can strongly affect mollusks' survival; however, physiological mechanisms of their combined effects are not fully understood. We studied the effects of Cd exposure on metabolic responses to prolonged anoxia and subsequent recovery in anoxia-tolerant intertidal mollusks Crassostrea virginica (eastern oysters). Anoxia led to an onset of anaerobiosis indicated by accumulation of L-alanine, acetate, and succinate. Prolonged anoxia (for 6 days) caused a decline in the maximum activity of electron transport chain and ADP-stimulated (state 3) oxygen uptake by mitochondria (MO 2), but no change in the resting (state 4) MO 2 of oyster mitochondria, along with a slight but significant reduction of mitochondrial respiratory control ratio. During reoxygenation, there was a significant overshoot of mitochondrial MO 2 (by up to 70% above the normoxic steady-state values) in control oysters. Mild mitochondrial uncoupling during prolonged shutdown in anoxic tissues and a subsequent strong stimulation of mitochondrial flux during recovery may help to rapidly restore redox status and protect against elevated reactive oxygen species formation in oysters. Exposure to Cd inhibits anaerobic metabolism, abolishes reoxygenation-induced stimulation of mitochondrial MO 2, and leads to oxidative stress (indicated by accumulation of DNA lesions) and a loss of mitochondrial capacity during postanoxic recovery. This may result in increased sensitivity to intermittent hypoxia and anoxia in Cd-exposed mollusks and will have implications for their survival in polluted estuaries and coastal zones. air exposure; recovery; mitochondrial function; oxidative damage; mollusks PERIODICAL OXYGEN DEFICIENCY is an important environmental stressor in intertidal and coastal habitats. Short-term intermittent hypoxia/anoxia (from several hours to several days, depending on the state of the tides) often occurs in intertidal invertebrates during the low tide, and may also occur in tidal pools and shallow lagoons with limited water exchange (8,36,49). Furthermore, long-term severe hypoxia and anoxia triggered by anthropogenic release of nutrients has become a serious issue in many estuaries and coastal zones rivaling the climate change (18,22). In the coastal dead zones, benthic invertebrates including mollusks can be exposed to severe hypoxia or anoxia for prolonged periods (from weeks to up to several months) (10,22,34,46). Long-term oxygen deficiency often leads to the massive die-offs in species with limited or...

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Section: Discussionsupporting

confidence: 56%

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Kurochkin

Ivanina

Eilers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Hu et al (17) have shown that hibernating myocardium have a significant reduction in mitochondrial function in vitro as reflected by a significant reduction in the respiratory control ratio mainly because of a decrease in state 3 respiration. This was also shown by Mc Falls et al (25) who studied isolated mitochondria from hibernating myocardium and demonstrated a decreased respiratory control ratio. They further demonstrated that the reduction in oxidant damage may also be related to an increase in uncoupling protein 2 in hibernating myocardium (25).…”

Section: Discussionsupporting

confidence: 69%

“…This was also shown by Mc Falls et al (25) who studied isolated mitochondria from hibernating myocardium and demonstrated a decreased respiratory control ratio. They further demonstrated that the reduction in oxidant damage may also be related to an increase in uncoupling protein 2 in hibernating myocardium (25).…”

Section: Discussionsupporting

confidence: 69%

Long-term preservation of myocardial energetic in chronic hibernating myocardium

Jameel

Mansoor

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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viously reported that the myocardial energetic state, as defined by the ratio of phosphocreatine to ATP (PCr/ATP), was preserved at baseline (BL) in a swine model of chronic myocardial ischemia with mild reduction of myocardial blood flow (MBF) 10 wk after the placement of an external constrictor on the left anterior descending coronary artery. It remains to be seen whether this stable energetic state is maintained at a longer-term follow-up. Hibernating myocardium (HB) was created in minipigs (n ϭ 7) by the placement of an external constrictor (1.25 mm internal diameter) on the left anterior descending coronary artery. Function was assessed with MRI at regular intervals until 6 mo. At 6 mo, myocardial energetic in the HB was assessed by 31 P-magnetic resonance spectrometry and myocardial oxygenation was examined from the deoxymyoglobin signal using 1 H-magnetic resonance spectrometry during BL, coronary vasodilation with adenosine, and high cardiac workload with dopamine and dobutamine (DpDb). MBF was measured with radiolabeled microspheres. At BL, systolic thickening fraction was significantly lower in the HB compared with remote region (34.4 Ϯ 9.4 vs. 50.1 Ϯ 10.7, P ϭ 0.006). This was associated with a decreased MBF in the HB compared with the remote region (0.73 Ϯ 0.08 vs. 0.97 Ϯ 0.07 ml·min Ϫ1 ·g, P ϭ 0.03). The HB PCr/ATP at BL was normal. DpDb resulted in a significant increase in rate pressure product, which caused a twofold increase in MBF in the HB and a threefold increase in the remote region. The systolic thickening fraction increased with DpDb, which was significantly higher in the remote region than HB (P Ͻ 0.05). The high cardiac workload was associated with a significant reduction in the HB PCr/ATP (P Ͻ 0.02), but this response was similar to normal myocardium. Thus HB has stable BL myocardial energetic despite the reduction MBF and regional left ventricular function. More importantly, HB has a reduced contractile reserve but has a similar energetic response to high cardiac workload like normal myocardium. spectroscopy IN CLINICAL PRACTICE, hibernating myocardium refers to areas of regional dysfunction, decreased blood flow, and absence of scar in patients with coronary artery disease who are thought to recover after revascularization (30 -31, 35). Hibernating myocardium is characterized by a balance between matched reductions in myocardial blood flow (MBF) and function (15, 16). The acute perfusion contraction matching in short-term hibernation is maintained up to 90 min after the initiation of moderate ischemia and is not sustained over several hours (15,16). In animal models, chronic hibernating myocardium can be created by a constriction of a proximal coronary artery that leads to a progressive reduction in MBF and regional dysfunction (3-5, 8 -9, 11-13, 23-25). Perfusion contraction matching in this model probably develops from single or repetitive bouts of stress-induced ischemia and reperfusion in the presence of severe coronary stenosis (15, 16). Thus there is a temporal progression from ...

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“…One possibility is that these changes are the result of a reduction in mitochondrial respiration, reflecting an intrinsic adaptation of the heart to repetitive ischemia. In support of this theory, McFalls et al (33) recently demonstrated a reduction in the RCR in mitochondria isolated from pigs with hibernating myocardium that results from insignificant reductions in state 3 respiration and increases in state 2 respiration. Our results provide further support for a primary mitochondrial adaptation by demonstrating a significant reduction in mitochondrial function in vitro.…”

Section: Discussionmentioning

confidence: 86%

Reductions in mitochondrial O₂consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium

Hu¹,

Suzuki²,

Young³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Reductions in mitochondrial O 2 consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium. Am J Physiol Heart Circ Physiol 297: H223-H232, 2009. First published April 24, 2009 doi:10.1152/ajpheart.00992.2008.-We performed the present study to determine whether hibernating myocardium is chronically protected from ischemia. Myocardial tissue was rapidly excised from hibernating left anterior descending coronary regions (systolic wall thickening ϭ 2.8 Ϯ 0.2 vs. 5.4 Ϯ 0.3 mm in remote myocardium), and high-energy phosphates were quantified by HPLC during simulated ischemia in vitro (37°C). At baseline, ATP (20.1 Ϯ 1.0 vs. 26.7 Ϯ 2.1 mol/g dry wt, P Ͻ 0.05), ADP (8.1 Ϯ 0.4 vs. 10.3 Ϯ 0.8 mol/g, P Ͻ 0.05), and total adenine nucleotides (31.2 Ϯ 1.3 vs. 40.1 Ϯ 2.9 mol/g, P Ͻ 0.05) were depressed compared with normal myocardium, whereas total creatine, creatine phosphate, and ATP-to-ADP ratios were unchanged. During simulated ischemia, there was a marked attenuation of ATP depletion (5.6 Ϯ 0.9 vs. 13.7 Ϯ 1.7 mol/g at 20 min in control, P Ͻ 0.05) and mitochondrial respiration [145 Ϯ 13 vs. 187 Ϯ 11 ng atoms O 2 ⅐ mg protein Ϫ1 ⅐ min Ϫ1 in control (state 3), P Ͻ 0.05], whereas lactate accumulation was unaffected. These in vitro changes were accompanied by protection of the hibernating heart from acute stunning during demand-induced ischemia. Thus, despite contractile dysfunction at rest, hibernating myocardium is ischemia tolerant, with reduced mitochondrial respiration and slowing of ATP depletion during simulated ischemia, which may maintain myocyte viability. energy metabolism; mitochondrial respiration; stunned myocardium ALTHOUGH REVERSIBLE MYOCARDIAL dysynergy can arise from a number of specific pathophysiological states, chronic hibernating myocardium is unique, in that it is characterized by regional contractile dysfunction and reduced resting flow in the absence of infarction (4, 18). In chronic hibernating myocardium, regional O 2 consumption is reduced at rest, as well as during increases in myocardial O 2 demand, yet evidence of acute myocardial ischemia is absent (11), which contrasts with findings in short-term hibernating myocardium (45,46). This appears to be partially related to a downregulation in many of the enzymes involved in oxidative metabolism and electron transport (39). Thus this regional dissociation between O 2 consumption and external workload protects the heart during submaximal increases in demand and attenuates apoptosisinduced myocyte loss in the chronic state.Collectively, these findings raise the possibility that hibernating myocardium may be chronically protected against ischemia. In support of this notion, Ausma et al.(1) demonstrated increased tolerance to ischemia in myocytes from hibernating myocardium. Similarly, Milei et al. (34) demonstrated a reduction in ischemia-reperfusion injury during cardiopulmonary bypass in hibernating myocardium compared with segments with normal systolic function. Unfortunately, these previo...

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Mitochondrial adaptations within chronically ischemic swine myocardium

Cited by 56 publications

References 42 publications

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Long-term preservation of myocardial energetic in chronic hibernating myocardium

Reductions in mitochondrial O₂consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium

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Mitochondrial adaptations within chronically ischemic swine myocardium

Cited by 56 publications

References 42 publications

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Long-term preservation of myocardial energetic in chronic hibernating myocardium

Reductions in mitochondrial O2consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium

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Reductions in mitochondrial O₂consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium