Alterations in mitochondrial function in cardiac hypertrophy and heart failure

Osterholt, Moritz; Nguyễn, Tiến Dũng; Schwarzer, Michael; Doenst, Torsten

doi:10.1007/s10741-012-9346-7

Cited by 62 publications

(41 citation statements)

References 118 publications

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“…ATP is primarily produced in the mitochondrial respiratory chain by OXPHOS. Previous studies showed that a dysfunction of mitochondrial bioenergetics contributes to the cardiac hypertrophy and can lead to heart failure (Wilkins et al ., ; Osterholt et al ., ). Mitochondrial changes during cardiac hypertrophy include disrupted mitochondrial substrate metabolism, respiratory chain activity and proteomic remodelling as well as oxidative stress (Marin‐Garcia et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Activation of TRPV1 attenuates high salt‐induced cardiac hypertrophy through improvement of mitochondrial function

Lang

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEHigh-salt diet induces cardiac remodelling and leads to heart failure, which is closely related to cardiac mitochondrial dysfunction. Transient receptor potential (TRP) channels are implicated in the pathogenesis of cardiac dysfunction. We investigated whether activation of TRP vanilloid (subtype 1) (TRPV1) channels by dietary capsaicin can, by ameliorating cardiac mitochondrial dysfunction, prevent high-salt diet-induced cardiac hypertrophy. EXPERIMENTAL APPROACH Male wild-type (WT) and TRPV1−/− mice were fed a normal or high-salt diet with or without capsaicin for 6 months. Their cardiac parameters and endurance capacity were assessed. Mitochondrial respiration and oxygen consumption were measured using high-resolution respirometry. The expression levels of TRPV1, sirtuin 3 and NDUFA9 were detected in cardiac cells and tissues. KEY RESULTSChronic high-salt diet caused cardiac hypertrophy and reduced physical activity in mice; both effects were ameliorated by capsaicin intake in WT but not in TRPV1 −/− mice. TRPV1 knockout or high-salt diet significantly jeopardized the proficiency of mitochondrial Complex I oxidative phosphorylation (OXPHOS) and reduced Complex I enzyme activity. Chronic dietary capsaicin increased cardiac mitochondrial sirtuin 3 expression, the proficiency of Complex I OXPHOS, ATP production and Complex I enzyme activity in a TRPV1-dependent manner. CONCLUSIONS AND IMPLICATIONSTRPV1 activation by dietary capsaicin can antagonize high-salt diet-mediated cardiac lesions by ameliorating its deleterious effect on the proficiency of Complex I OXPHOS. TRPV1-mediated amendment of mitochondrial dysfunction may represent a novel target for management of early cardiac dysfunction.

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Section: Discussionmentioning

confidence: 97%

Activation of TRPV1 attenuates high salt‐induced cardiac hypertrophy through improvement of mitochondrial function

Lang

et al. 2015

British J Pharmacology

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“…Finally, it should be noted that four out the nine patients had left ventricular hypertrophy. Mitochondrial function could therefore be further deteriorated (26,32) apart from the ischemia related dysfunction, but because of the limited number of patients, meaningful subgroup analyses could not be done.…”

Section: Discussionmentioning

confidence: 99%

Impaired mitochondrial function in chronically ischemic human heart

Stride

Larsen

Hey-Mogensen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Chronic ischemic heart disease is associated with myocardial hypoperfusion. The resulting hypoxia potentially inflicts damage upon the mitochondria, leading to a compromised energetic state. Furthermore, ischemic damage may cause excessive production of reactive oxygen species (ROS), producing mitochondrial damage, hereby reinforcing a vicious circle. Ischemic preconditioning has been proven protective in acute ischemia, but the subject of chronic ischemic preconditioning has not been explored in humans. We hypothesized that mitochondrial respiratory capacity would be diminished in chronic ischemic regions of human myocardium but that these mitochondria would be more resistant to ex vivo ischemia and, second, that ROS generation would be higher in ischemic myocardium. The aim of this study was to test mitochondrial respiratory capacity during hyperoxia and hypoxia, to investigate ROS production, and finally to assess myocardial antioxidant levels. Mitochondrial respiration in biopsies from ischemic and nonischemic regions from the left ventricle of the same heart was compared in nine human subjects. Maximal oxidative phosphorylation capacity in fresh muscle fibers was lower in ischemic compared with nonischemic myocardium (P Ͻ 0.05), but the degree of coupling (respiratory control ratio) did not differ (P Ͼ 0.05). The presence of ex vivo hypoxia did not reveal any chronic ischemic preconditioning of the ischemic myocardial regions (P Ͼ 0.05). ROS production was higher in ischemic myocardium (P Ͻ 0.05), and the levels of antioxidant protein expression was lower. Diminished mitochondrial respiration capacity and excessive ROS production demonstrate an impaired mitochondrial function in ischemic human heart muscle. No chronic ischemic preconditioning effect was found. mitochondrial respiration; reactive oxygen species; left ventricle CHRONIC ISCHEMIC HEART DISEASE (IHD) is caused by progressive atherosclerosis of the coronary arteries, leading to regional hypoperfusion of the myocardium. This results in local hypoxia that potentially limits ATP production from the processes of oxidative phosphorylation (OXPHOS) in mitochondria (4,8,12). Furthermore, acute ischemia and reperfusion causes mitochondrial dysfunction and subsequent excessive production of reactive oxygen species (ROS) by the electron transport chain (ETC) (23). Blockade of complex I or III in the ETC decreases ROS production during episodes of ischemia and helps protect the mitochondria against ischemic damage (2, 9), whereas blockade at a step distal of complex III [site of cytochrome c oxidase (COX)] has been shown to increase ROS generation (9). Traditionally (5), complexes I and III are regarded as the primary sources of ROS (within the ETC), but recently complex II has also been shown to produce ROS, at least in skeletal muscle (31). The deleterious actions of ROS include damage to the mitochondrial membrane constituents (lipids and proteins) and mtDNA (28), opening of mitochondrial permeability transition pores, resulting in mitochondrial depolari...

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“…As the engine of the generation of energy and reactive oxygen species (ROS) [12], the mitochondrion plays an important role in the myocardium. The heart, which is an organ with a high energy consumption, also exhibits changes or impairment in mitochondrial function during the progression of hypertrophy or heart failure [13]. Some studies reported that treatment with atorvastatin could regulate the metabolism of the myocardium [14].…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin Attenuates Myocardial Hypertrophy in Spontaneously Hypertensive Rats via the C/EBPβ/PGC-1α/UCP3 Pathway

Chen¹,

Chang²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Many clinical and experimental studies have shown that treatment with statins could prevent myocardial hypertrophy and remodeling induced by hypertension and myocardial infarction. But the molecular mechanism was not clear. We aimed to investigate the beneficial effects of atorvastatin on hypertension-induced myocardial hypertrophy and remodeling in spontaneously hypertensive rats (SHR) with the hope of revealing other potential mechanisms or target pathways to interpret the pleiotropic effects of atorvastatin on myocardial hypertrophy. Methods: The male and age-matched animals were randomly divided into three groups: control group (8 WKY), SHR (8 rats) and intervention group (8 SHR). The SHR in intervention group were administered by oral gavage with atorvastatin (suspension in distilled water, 10 mg/Kg once a day) for 6 weeks, and the other two groups were administered by gavage with equal quantity distilled water. Blood pressure of rats was measured every weeks using a standard tail cuff sphygmomanometer. Left ventricular (LV) dimensions were measured from short-axis views of LV under M-mode tracings using Doppler echocardiograph. Cardiomyocyte apoptosis was assessed by the TUNEL assay. The protein expression of C/EBPβ, PGC-1α and UCP3 were detected by immunohistochemistry or Western blot analysis. Results: At the age of 16 weeks, the mean arterial pressure of rats in three groups were 103.6±6.1, 151.8±12.5 and 159.1±6.2 mmHg respectively, and there wasn’t statistically significant difference between the SHR and intervention groups. Staining with Masson’s trichrome demonstrated that the increased interstitial fibrosis of LV and ventricular remodeling in the SHR group were attenuated by atorvastatin treatment. Echocardiography examination exhibited that SHR with atorvastatin treatment showed an LV wall thickness that was obviously lower than that of water-treated SHR. In hypertrophic myocardium, accompanied by increasing C/EBPβ expression and the percentage of TUNEL-positive cells, the expression of Bcl-2/Bax ratio, PGC-1α and UCP3 were reduced, all of which could be abrogated by treatment with atorvastatin for 6 weeks. Conclusion: This study further confirmed that atorvastatin could attenuate myocardial hypertrophy and remodeling in SHR by inhibiting apoptosis and reversing changes in mitochondrial metabolism. The C/EBPβ/PGC-1α/UCP3 signaling pathway might also be important for elucidating the beneficial pleiotropic effects of atorvastatin on myocardial hypertrophy.

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Alterations in mitochondrial function in cardiac hypertrophy and heart failure

Cited by 62 publications

References 118 publications

Activation of TRPV1 attenuates high salt‐induced cardiac hypertrophy through improvement of mitochondrial function

Activation of TRPV1 attenuates high salt‐induced cardiac hypertrophy through improvement of mitochondrial function

Impaired mitochondrial function in chronically ischemic human heart

Atorvastatin Attenuates Myocardial Hypertrophy in Spontaneously Hypertensive Rats via the C/EBPβ/PGC-1α/UCP3 Pathway

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