International Journal of Molecular Sciences

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3 pages, 203 KiB

Open AccessEditorial

Protecting the Mitochondria in Cardiac Disease

by Antigone Lazou and Chrishan J. Ramachandra

Int. J. Mol. Sci. 2022, 23(15), 8115; https://doi.org/10.3390/ijms23158115 - 23 Jul 2022

Cited by 2 | Viewed by 1284

Abstract

Cardiac disease is a broad cluster of several diseases, which include coronary artery disease, valve disease, congenital heart disease, arrhythmia, and cardiomyopathy [...] Full article

(This article belongs to the Special Issue Bioenergetics, Mitochondrial Dynamics and Cardiac Disease)

Research

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16 pages, 1983 KiB

Open AccessArticle

Cardioprotection of Immature Heart by Simultaneous Activation of PKA and Epac: A Role for the Mitochondrial Permeability Transition Pore

by Martin John Lewis, Igor Khaliulin, Katie Hall and M. Saadeh Suleiman

Int. J. Mol. Sci. 2022, 23(3), 1720; https://doi.org/10.3390/ijms23031720 - 2 Feb 2022

Cited by 3 | Viewed by 1552

Abstract

Metabolic and ionic changes during ischaemia predispose the heart to the damaging effects of reperfusion. Such changes and the resulting injury differ between immature and adult hearts. Therefore, cardioprotective strategies for adults must be tested in immature hearts. We have recently shown that [...] Read more.

Metabolic and ionic changes during ischaemia predispose the heart to the damaging effects of reperfusion. Such changes and the resulting injury differ between immature and adult hearts. Therefore, cardioprotective strategies for adults must be tested in immature hearts. We have recently shown that the simultaneous activation of protein kinase A (PKA) and exchange protein activated by cAMP (Epac) confers marked cardioprotection in adult hearts. The aim of this study is to investigate the efficacy of this intervention in immature hearts and determine whether the mitochondrial permeability transition pore (MPTP) is involved. Isolated perfused Langendorff hearts from both adult and immature rats were exposed to global ischaemia and reperfusion injury (I/R) following control perfusion or perfusion after an equilibration period with activators of PKA and/or Epac. Functional outcome and reperfusion injury were measured and in parallel, mitochondria were isolated following 5 min of reperfusion to determine whether cardioprotective interventions involved changes in MPTP opening behaviour. Perfusion for 5 min preceding ischaemia of injury-matched adult and immature hearts with 5 µM 8-Br (8-Br-cAMP-AM), an activator of both PKA and Epac, led to significant reduction in post-reperfusion CK release and infarct size. Perfusion with this agent also led to a reduction in MPTP opening propensity in both adult and immature hearts. These data show that immature hearts are innately more resistant to I/R injury than adults, and that this is due to a reduced tendency of MPTP opening following reperfusion. Furthermore, simultaneous stimulation of PKA and Epac causes cardioprotection, which is additive to the innate resistance. Full article

(This article belongs to the Special Issue Bioenergetics, Mitochondrial Dynamics and Cardiac Disease)

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17 pages, 2853 KiB

Open AccessArticle

Cardioprotective Effects of PPARβ/δ Activation against Ischemia/Reperfusion Injury in Rat Heart Are Associated with ALDH2 Upregulation, Amelioration of Oxidative Stress and Preservation of Mitochondrial Energy Production

by Ioanna Papatheodorou, Eleftheria Galatou, Georgios-Dimitrios Panagiotidis, Táňa Ravingerová and Antigone Lazou

Int. J. Mol. Sci. 2021, 22(12), 6399; https://doi.org/10.3390/ijms22126399 - 15 Jun 2021

Cited by 19 | Viewed by 2625

Abstract

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor β/δ (PPARβ/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARβ/δ-mediated cardioprotection in the setting of [...] Read more.

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor β/δ (PPARβ/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARβ/δ-mediated cardioprotection in the setting of myocardial ischemia/reperfusion (I/R). For this purpose, rats were treated with PPARβ/δ agonist GW0742 and/or antagonist GSK0660 in vivo and hearts were subjected to ex vivo global ischemia followed by reperfusion. PPARβ/δ activation improved left ventricular developed pressure recovery, reduced infarct size (IS) and incidence of reperfusion-induced ventricular arrhythmias while it also up-regulated superoxide dismutase 2, catalase and uncoupling protein 3 resulting in attenuation of oxidative stress as evidenced by the reduction in 4-hydroxy-2-nonenal protein adducts and protein carbonyl formation. PPARβ/δ activation also increased both mRNA expression and enzymatic activity of aldehyde dehydrogenase 2 (ALDH2); inhibition of ALDH2 abrogated the IS limiting effect of PPARβ/δ activation. Furthermore, upregulation of PGC-1α and isocitrate dehydrogenase 2 mRNA expression, increased citrate synthase activity as well as mitochondrial ATP content indicated improvement in mitochondrial content and energy production. These data provide new mechanistic insight into the cardioprotective properties of PPARβ/δ in I/R pointing to ALDH2 as a direct downstream target and suggesting that PPARβ/δ activation alleviates myocardial I/R injury through coordinated stimulation of the antioxidant defense of the heart and preservation of mitochondrial function. Full article

(This article belongs to the Special Issue Bioenergetics, Mitochondrial Dynamics and Cardiac Disease)

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15 pages, 1026 KiB

Open AccessArticle

Lack of Contribution of p66shc to Pressure Overload-Induced Right Heart Hypertrophy

by Christine Hirschhäuser, Akylbek Sydykov, Annemarie Wolf, Azadeh Esfandiary, Julia Bornbaum, Hanna Sarah Kutsche, Kerstin Boengler, Natascha Sommer, Rolf Schreckenberg, Klaus-Dieter Schlüter, Norbert Weissmann, Ralph Schermuly and Rainer Schulz

Int. J. Mol. Sci. 2020, 21(24), 9339; https://doi.org/10.3390/ijms21249339 - 8 Dec 2020

Cited by 6 | Viewed by 1884

Abstract

The leading cause of death in pulmonary arterial hypertension (PAH) is right ventricular (RV) failure (RVF). Reactive oxygen species (ROS) have been suggested to play a role in the development of RV hypertrophy (RVH) and the transition to RVF. The hydrogen peroxide-generating protein [...] Read more.

The leading cause of death in pulmonary arterial hypertension (PAH) is right ventricular (RV) failure (RVF). Reactive oxygen species (ROS) have been suggested to play a role in the development of RV hypertrophy (RVH) and the transition to RVF. The hydrogen peroxide-generating protein p66shc has been associated with left ventricular (LV) hypertrophy but its role in RVH is unclear. The purpose of this study was to determine whether genetic deletion of p66shc affects the development and/or progression of RVH and RVF in the pulmonary artery banding (PAB) model of RV pressure overload. The impact of p66shc on mitochondrial ROS formation, RV cardiomyocyte function, as well as on RV morphology and function were studied three weeks after PAB or sham operation. PAB in wild type mice did not affect mitochondrial ROS production or RV cardiomyocyte function, but induced RVH and impaired cardiac function. Genetic deletion of p66shc did also not alter basal mitochondrial ROS production or RV cardiomyocyte function, but impaired RV cardiomyocyte shortening was observed following PAB. The development of RVH and RVF following PAB was not affected by p66shc deletion. Thus, our data suggest that p66shc-derived ROS are not involved in the development and progression of RVH or RVF in PAH. Full article

(This article belongs to the Special Issue Bioenergetics, Mitochondrial Dynamics and Cardiac Disease)

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11 pages, 1710 KiB

Open AccessArticle

Fingolimod (FTY720) Preserves High Energy Phosphates and Improves Cardiac Function in Heterotopic Heart Transplantation Model

by Naseer Ahmed, Javeria Farooq, Soban Sadiq, Sultan Ayoub Meo, Azam Jan, Faisal H. Cheema, Giuseppe Faggian and Alessio Rungatscher

Int. J. Mol. Sci. 2020, 21(18), 6548; https://doi.org/10.3390/ijms21186548 - 8 Sep 2020

Cited by 6 | Viewed by 2648

Abstract

During heart transplantation, donor heart leads to reduced oxygen supply resulting in low level of high energy phosphate (HEP) reserves in cardiomyocyte. Lower HEP is one of the underlying reasons of cell death due to ischemia. In this study we investigated the role [...] Read more.

During heart transplantation, donor heart leads to reduced oxygen supply resulting in low level of high energy phosphate (HEP) reserves in cardiomyocyte. Lower HEP is one of the underlying reasons of cell death due to ischemia. In this study we investigated the role of Fingolimod (FTY720) in heart transplantation ischemia. Eight groups of Sprague-Dawley rats (n = 5 for each subgroup) were made, A1 and C1 were given FTY720 1 mg/kg while B1 and D1 were given normal saline. The hearts were implanted into another set of similar rats after preservation period of 1 h at 4–8 °C. Significantly higher Left ventricular systolic pressure (LVSP), dP/dT maximum (p < 0.05), dP/dT minimum (p < 0.05) were recorded in the FTY720 treated group after 24 h of reperfusion while after 1 h of reperfusion, there were no significant differences in LVSP, maximum and negative dP/dT, and Left ventricular end diastolic pressure (LVEDP) between the control and the FTY720-treated transplant groups. Coronary blood flow (CBF) was enhanced (p < 0.05) in the FTY720 treated group after 1 and 24 h. ATP p < 0.001, p < 0.05 at 1 and 24 h, ADP p < 0.001, p > 0.05 at 1 and 24 h, and phosphocreatine p < 0.05, p > 0.05 at 1 and 24 h were better preserved by FTY720 treatment as compared to control group. The study concluded that pretreatment of grafted hearts with FTY720 improved hemodynamics, CBF, high energy phosphate reserves, reduces the peroxynitrite level and poly (ADP ribose) polymerase (PARP) inhibition that prevents ischemia-reperfusion injury. Full article

(This article belongs to the Special Issue Bioenergetics, Mitochondrial Dynamics and Cardiac Disease)

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Review

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19 pages, 2506 KiB

Open AccessReview

Oestrogenic Regulation of Mitochondrial Dynamics

by Siavash Beikoghli Kalkhoran and Georgios Kararigas

Int. J. Mol. Sci. 2022, 23(3), 1118; https://doi.org/10.3390/ijms23031118 - 20 Jan 2022

Cited by 20 | Viewed by 3474

Abstract

Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central [...] Read more.

Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion–fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems. Full article

(This article belongs to the Special Issue Bioenergetics, Mitochondrial Dynamics and Cardiac Disease)

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20 pages, 2374 KiB

Open AccessReview

Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium

by Tom Kretzschmar, Jasmine M. F. Wu and P. Christian Schulze

Int. J. Mol. Sci. 2021, 22(3), 1498; https://doi.org/10.3390/ijms22031498 - 2 Feb 2021

Cited by 9 | Viewed by 3486

Abstract

Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more [...] Read more.

Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis. Full article

(This article belongs to the Special Issue Bioenergetics, Mitochondrial Dynamics and Cardiac Disease)

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19 pages, 560 KiB

Open AccessReview

Mitochondrial Dysfunction and Heart Disease: Critical Appraisal of an Overlooked Association

by Giandomenico Bisaccia, Fabrizio Ricci, Sabina Gallina, Angela Di Baldassarre and Barbara Ghinassi

Int. J. Mol. Sci. 2021, 22(2), 614; https://doi.org/10.3390/ijms22020614 - 9 Jan 2021

Cited by 31 | Viewed by 8651

Abstract

The myocardium is among the most energy-consuming tissues in the body, burning from 6 to 30 kg of ATP per day within the mitochondria, the so-called powerhouse of the cardiomyocyte. Although mitochondrial genetic disorders account for a small portion of cardiomyopathies, mitochondrial dysfunction [...] Read more.

The myocardium is among the most energy-consuming tissues in the body, burning from 6 to 30 kg of ATP per day within the mitochondria, the so-called powerhouse of the cardiomyocyte. Although mitochondrial genetic disorders account for a small portion of cardiomyopathies, mitochondrial dysfunction is commonly involved in a broad spectrum of heart diseases, and it has been implicated in the development of heart failure via maladaptive circuits producing and perpetuating mitochondrial stress and energy starvation. In this bench-to-bedside review, we aimed to (i) describe the key functions of the mitochondria within the myocardium, including their role in ischemia/reperfusion injury and intracellular calcium homeostasis; (ii) examine the contribution of mitochondrial dysfunction to multiple cardiac disease phenotypes and their transition to heart failure; and (iii) discuss the rationale and current evidence for targeting mitochondrial function for the treatment of heart failure, including via sodium-glucose cotransporter 2 inhibitors. Full article

(This article belongs to the Special Issue Bioenergetics, Mitochondrial Dynamics and Cardiac Disease)

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