Acute metformin treatment provides cardioprotection via improved mitochondrial function in cardiac ischemia / reperfusion injury

Palee, Siripong; Higgins, Louis; Leech, Tom; Chattipakorn, Nipon

doi:10.1016/j.biopha.2020.110604

Cited by 18 publications

(11 citation statements)

References 39 publications

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“…PGC-1α is thought to serve as a vital regulator of mitochondrial biogenesis and function, and metformin could upregulate its expression by AMPK activation in I/R injury mice, 69 then normalize shape and structure of mitochondria, and balance mitochondrial dynamics. 73,81 The mitochondrial permeability transition pore (mPTP) is a non-specific channel on the mitochondrial inner membrane, whose opening will result in cardiomyocytes death in the first few minutes of myocardial reperfusion. 82 The opening of mPTP is controlled by the Cyclophilin D (CypD), a master regulator of mitochondrial function.…”

Section: Ex In Vivo Outcomes and Ampk-related Actions Of Metformin In...mentioning

confidence: 99%

“…In addition, metformin also could exert cardio‐protective effects with an extremely short administration time in acute condition 71,72 . Furthermore, Palee et al observed that 200 mg/kg of metformin achieved the optimal effects on reducing infarct size compared to 100 and 400 mg/kg of metformin 73 …”

Section: Effects Of Metformin In Heart Diseasesmentioning

confidence: 99%

“…71,72 Furthermore, Palee et al observed that 200 mg/kg of metformin achieved the optimal effects on reducing infarct size compared to 100 and 400 mg/kg of metformin. 73 In contrast, several conflicting observations of animal studies have been reported. In acute MI mouse models, administration of 100, 200 and 400 mg/kg of metformin for 1 week caused a significant increase rather than decrease in mortality of the MI mice in a dose-dependent manner.…”

Section: Ex In Vivo Outcomes and Ampk-related Actions Of Metformin In...mentioning

confidence: 99%

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Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK‐dependent mechanisms

Peng

Tang

et al. 2022

J Cellular Molecular Medi

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Metformin, a well‐known AMPK agonist, has been widely used as the first‐line drug for treating type 2 diabetes. There had been a significant concern regarding the use of metformin in people with cardiovascular diseases (CVDs) due to its potential lactic acidosis side effect. Currently growing clinical and preclinical evidence indicates that metformin can lower the incidence of cardiovascular events in diabetic patients or even non‐diabetic patients beyond its hypoglycaemic effects. The underlying mechanisms of cardiovascular benefits of metformin largely involve the cellular energy sensor, AMPK, of which activation corrects endothelial dysfunction, reduces oxidative stress and improves inflammatory response. In this minireview, we summarized the clinical evidence of metformin benefits in several widely studied cardiovascular diseases, such as atherosclerosis, ischaemic/reperfusion injury and arrhythmia, both in patients with or without diabetes. Meanwhile, we highlighted the potential AMPK‐dependent mechanisms in in vitro and/or in vivo models.

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Section: Ex In Vivo Outcomes and Ampk-related Actions Of Metformin In...mentioning

confidence: 99%

Section: Effects Of Metformin In Heart Diseasesmentioning

confidence: 99%

Section: Ex In Vivo Outcomes and Ampk-related Actions Of Metformin In...mentioning

confidence: 99%

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Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK‐dependent mechanisms

Peng

Tang

et al. 2022

J Cellular Molecular Medi

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“…(*) Metformin, in addition to its effect on AMPK signaling pathway, was shown to have biphasic effects on mitochondria: at low concentrations it affects on oxygen consumption rate (OCR) and mitochondrial biogenesis of cardiomyocytes and at high concentrations in isolated human cardiac mitochondria it attenuates superoxide production and it inhibits Ca 2+ -induced mPTP opening ( Emelyanova et al, 2021 ). This hypoglycemic drug has been shown to have cardioprotective effects in murine cardiac transplantation models limiting acute IRI ( Chin et al, 2011 ) and, in rats undergoing cardiac I/R, metformin treatment ameliorates overall cardiac function after the reduction of mitochondrial fission, ROS production, apoptosis and mitochondrial swelling ( Palee et al, 2020 ). Summarizing, even if several preclinical and clinical studies have suggested cardioprotective effects of metformin treatment ( Holman et al, 2008 ; Mellbin et al, 2008 ), others have shown no beneficial long-term effects of this drug ( Hartman et al, 2017 ).…”

Section: Recent Clinical Strategies Based On Targeting Mitochondriamentioning

confidence: 99%

Perspectives on mitochondrial relevance in cardiac ischemia/reperfusion injury

Pedriali

Ramaccini

Bouhamida

et al. 2022

Front. Cell Dev. Biol.

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Cardiovascular disease is the most common cause of death worldwide and in particular, ischemic heart disease holds the most considerable position. Even if it has been deeply studied, myocardial ischemia-reperfusion injury (IRI) is still a side-effect of the clinical treatment for several heart diseases: ischemia process itself leads to temporary damage to heart tissue and obviously the recovery of blood flow is promptly required even if it worsens the ischemic injury. There is no doubt that mitochondria play a key role in pathogenesis of IRI: dysfunctions of these important organelles alter cell homeostasis and survival. It has been demonstrated that during IRI the system of mitochondrial quality control undergoes alterations with the disruption of the complex balance between the processes of mitochondrial fusion, fission, biogenesis and mitophagy. The fundamental role of mitochondria is carried out thanks to the finely regulated connection to other organelles such as plasma membrane, endoplasmic reticulum and nucleus, therefore impairments of these inter-organelle communications exacerbate IRI. This review pointed to enhance the importance of the mitochondrial network in the pathogenesis of IRI with the aim to focus on potential mitochondria-targeting therapies as new approach to control heart tissue damage after ischemia and reperfusion process.

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“…Modern medicine restores myocardial perfusion through either percutaneous coronary intervention or thrombolytic therapy, and both of these have brought about a new problem that aggravates cardiomyocyte damage: ischemia/reperfusion injury ( Kolwicz et al, 2013 ). It has been shown that diabetic patients suffered severer damage from ischemia/reperfusion injury ( Marfella et al, 2002 ; Palee et al, 2020 ). The mechanisms underlying the increased vulnerability of cardiomyocytes in diabetic patients remained unknown.…”

Section: Introductionmentioning

confidence: 99%

High Glucose Attenuates Cardioprotective Effects of Glucagon-Like Peptide-1 Through Induction of Mitochondria Dysfunction via Inhibition of β-Arrestin-Signaling

Pan¹,

Gao

2021

Front. Physiol.

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An increased vulnerability has been detected after ischemia/reperfusion injury in cardiomyocytes in diabetic patients. Glucagon-like peptide-1 (GLP-1) has been proven to have a notable cardioprotective effect in cardiomyocytes. However, in diabetic patients, the cardioprotective effects of GLP-1 are compromised, which is called GLP-1 resistance. β-arrestin is one of the two main downstream effectors of GLP-1 and β-arrestin signaling pathway exerts cardioprotective effects upon activation of GLP-1R. Our hypothesis is that the increased vulnerability of cardiomyocytes in diabetic patients is partly due to disruption of the β-arrestin signaling pathway. To test this, we analyzed cardiomyocyte viability and survival in high glucose and normal glucose condition after hypoxia/reoxygenation injury in vitro, additional GLP-1 was used to determine whether β-arrestin signaling pathway was involved. We also investigated the role of mitochondrial dysfunction in GLP-1 resistance. Our results showed that cardioprotective effects of GLP-1 were reduced in high glucose cultured H9C2 cells compared to normal glucose cultured H9C2, verifying the existence of GLP-1 resistance in high glucose cultured H9C2 cells. Further study suggested that β-arrestin plays a key role in GLP-1 resistance: β-arrestin expression is notably downregulated in high glucose condition and cardioprotective effects of GLP-1 can be diminished by downregulation of β-arrestin in normal glucose condition while upregulation of β-arrestin can restore cardioprotective effects of GLP-1 in high glucose condition. Then we explore how β-arrestin affects the cardioprotective effects of GLP-1 and found that β-arrestin exerts cardioprotective effects by improving mitochondria quality control via the PI3K/Akt signaling pathway. Thus, our study found out a new mechanism of GLP-1 resistance of cardiomyocytes in high glucose conditions that impaired β-arrestin expression, caused mitochondria dysfunction and eventually cell death. Our study provided a new perspective in treating myocardial ischemia/reperfusion injury in diabetic patients.

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Acute metformin treatment provides cardioprotection via improved mitochondrial function in cardiac ischemia / reperfusion injury

Cited by 18 publications

References 39 publications

Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK‐dependent mechanisms

Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK‐dependent mechanisms

Perspectives on mitochondrial relevance in cardiac ischemia/reperfusion injury

High Glucose Attenuates Cardioprotective Effects of Glucagon-Like Peptide-1 Through Induction of Mitochondria Dysfunction via Inhibition of β-Arrestin-Signaling

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