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Background — A shared feature among cardiovascular disease risk factors is increased oxidative stress. Because mitochondria are susceptible to damage mediated by oxidative stress, we hypothesized that risk factors (secondhand smoke and hypercholesterolemia) are associated with increased mitochondrial damage in cardiovascular tissues. Methods and Results — Atherosclerotic lesion formation, mitochondrial DNA damage, protein nitration, and specific activities of mitochondrial proteins in cardiovascular tissues from age-matched C57 and apoE −/− mice exposed to filtered air or secondhand smoke were quantified. Both secondhand smoke and hypercholesterolemia were associated with significantly increased mitochondrial DNA damage and protein nitration. Tobacco smoke exposure also resulted in significantly decreased specific activities of mitochondrial enzymes. The combination of secondhand smoke and hypercholesterolemia resulted in increased atherosclerotic lesion formation and even greater levels of mitochondrial damage. Conclusions — These data are consistent with the hypothesis that cardiovascular disease risk factors cause mitochondrial damage and dysfunction.
Objective: Reperfusion injury accounts for ~50% of myocardial infarct size, and meaningful clinical therapies targeting this do not exist. We have shown that HDAC inhibition-enhanced cardiomyocyte autophagy blunts ischemia/reperfusion (I/R) injury given at the time of reperfusion. However, as HDAC inhibition may have off-target effects, we set out to test whether augmentation of autophagy protects myocardium through maintenance of mitochondrial homeostasis and reduction of oxidative stress during reperfusion injury. Methods: 10-week-old, wild-type, C57BL6 mice were randomized into 3 groups: vehicle control, or exposed to a Tat-Scrambled (TS) peptide, or a Tat-Beclin (TB, autophagy-inducing molecule) peptide. Each group was subjected to I/R surgery (45min coronary ligation, 24h reperfusion). Infarct size, systolic function, and mitochondrial dynamics were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were exposed to TB during simulated ischemia/reperfusion injury. ATG7 knockout (ATG7 KO) mice and ATG7 knockdown by siRNA in NRVMs was used to evaluate the role of autophagy. Results: TB treatment at reperfusion reduced infarct size by 20.1% (n=23, p<0.05) and improved systolic function (n=11, p<0.05). Improvement correlated with increased autophagic flux in the border zone with less oxidative stress. ATG7 KO mice did not manifest TB-promoted cardioprotection during I/R. TB increased mtDNA content in the border zone (n=10, p<0.05). In NRVMs subjected to I/R, TB reduced cell death by 41% (n=12, p<0.001), reduced I/R-induced mtDNA damage, and increased mtDNA content by >60% (n=3, p<0.05). Moreover, TB promoted expression of the gene coding for PGC-1α, which controls mitochondrial biogenesis, in the border zone (n=10, p<0.05) and in NRVMs subjected to I/R (n=3, p<0.05), along with expression of the mitochondrial dynamics genes Drp1, Fis1 and MFN1 / 2 (n=9, p<0.05). Conversely, ATG7 knockdown in NRVMs abolished these beneficent effects of TB on mitochondria. Conclusions: Autophagy is a sufficient and essential process to mitigate reperfusion injury through maintenance of mitochondrial homeostasis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in myocardial infarction
Abstract Rationale: Oxidant stress contributes significantly to the pathogenesis of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. Mitochondrial function regulates oxidant stress responses as well as pluripotency and regenerative ability of mesenchymal stem cells (MSCs) which are critical mediators of lung development. Objective: To test whether differences in endogenous MSC mitochondrial bioenergetics, proliferation and survival are associated with BPD risk in ELBW infants. Findings: Umbilical cord-derived MSCs of ELBW infants who later died or developed moderate/severe BPD had lower oxygen consumption and aconitase activity but higher extracellular acidification - indicative of mitochondrial dysfunction and increased oxidant stress vs. MSCs from infants who survived with no/mild BPD. Hyperoxia-exposed MSCs from infants who died or developed moderate/severe BPD also had lower PINK1 expression but higher TOM20 expression and numbers of mitochondria/cell, indicative of decreased mitophagy. Finally, these MSCs were noted to proliferate at lower rates but undergo more apoptosis in cell cultures when compared to MSCs from infants who survived with no/mild BPD. Conclusions: These results indicate that mitochondrial bioenergetic dysfunction and mitophagy deficit induced by oxidant stress may lead to depletion of the endogenous MSC pool and subsequent disruption of lung development in ELBW infants at increased risk for BPD.
Abstract Oxidant stress contributes significantly to the pathogenesis of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. Mitochondrial function regulates oxidant stress responses as well as pluripotency and regenerative ability of mesenchymal stem cells (MSCs) which are critical mediators of lung development. This study was conducted to test whether differences in endogenous MSC mitochondrial bioenergetics, proliferation and survival are associated with BPD risk in ELBW infants. Umbilical cord-derived MSCs of ELBW infants who later died or developed moderate/severe BPD had lower oxygen consumption and aconitase activity but higher extracellular acidification—indicative of mitochondrial dysfunction and increased oxidant stress—when compared to MSCs from infants who survived with no/mild BPD. Hyperoxia-exposed MSCs from infants who died or developed moderate/severe BPD also had lower PINK1 expression but higher TOM20 expression and numbers of mitochondria/cell, indicating that these cells had decreased mitophagy. Finally, these MSCs were also noted to proliferate at lower rates but undergo more apoptosis in cell cultures when compared to MSCs from infants who survived with no/mild BPD. These results indicate that mitochondrial bioenergetic dysfunction and mitophagy deficit induced by oxidant stress may lead to depletion of the endogenous MSC pool and subsequent disruption of lung development in ELBW infants at increased risk for BPD.
Xanthine oxidase (XO) is increased in human and rat left ventricular (LV) myocytes with volume overload (VO) of mitral regurgitation and aortocaval fistula (ACF). In the setting of increased ATP demand, XO-mediated ROS can decrease mitochondrial respiration and contractile function. Thus, we tested the hypothesis that XO inhibition improves cardiomyocyte bioenergetics and LV function in chronic ACF in the rat. Sprague-Dawley rats were randomized to either sham or ACF ± allopurinol (100 mg·kg −1 ·day −1 , n ≥7 rats/group). Echocardiography at 8 wk demonstrated a similar 37% increase in LV end-diastolic dimension ( P < 0.001), a twofold increase in LV end-diastolic pressure/wall stress ( P < 0.05), and a twofold increase in lung weight ( P < 0.05) in treated and untreated ACF groups versus the sham group. LV ejection fraction, velocity of circumferential shortening, maximal systolic elastance, and contractile efficiency were significantly depressed in ACF and significantly improved in ACF + allopurinol rats, all of which occurred in the absence of changes in the maximum O 2 consumption rate measured in isolated cardiomyocytes using the extracellular flux analyzer. However, the improvement in contractile function is not paralleled by any attenuation in LV dilatation, LV end-diastolic pressure/wall stress, and lung weight. In conclusion, allopurinol improves LV contractile function and efficiency possibly by diminishing the known XO-mediated ROS effects on myofilament Ca 2+ sensitivity. However, LV remodeling and diastolic properties are not improved, which may explain the failure of XO inhibition to improve symptoms and hospitalizations in patients with severe heart failure.
<p>PDF file - 1105K, Supplemental Figure 7. KISS1 inhibits glucose uptake and activation of AMPK. A, Glucose uptake by C8161.9Vector (Vec), C8161.9KFMΔSS, C8161.9KFM and C8161.9KFM/shPGC1α cells was measured using 2-deoxyglucose uptake and normalized to total protein. B, C8161.9Vector, C8161.9KFM and C8161.9KFMdeltaSS cells were treated with AICAR followed by Western blot with antibodies for AMPK, phospho-AMPK (Thr172), mTOR , phospho-mTOR (Ser2448), KISS1 and GAPDH.</p>
