Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and Restored by Empagliflozin

Juni, Rio P.; Kuster, Diederik W.D.; Goebel, Max; Helmes, Michiel; Musters, René J.P.; Velden, Jolanda van der; Koolwijk, Pieter; Paulus, Walter J.; Hinsbergh, Victor W.M. van

doi:10.1016/j.jacbts.2019.04.003

Cited by 151 publications

(155 citation statements)

References 59 publications

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“…demonstrated that Empagliflozin suppresses TNF-α-induced mitochondrial and cytoplasmic ROS accumulation, thereby restoring cardiac microvascular endothelial cell-derived NO delivery, which in turn leads to reinstatement of cardiac relaxation and contraction (79). There are great expectations regarding the result of these clinical trials because, at the time of writing, no drugs have been demonstrated to be effective for the treatment of HFpEF (80).…”

Section: Future Directionsmentioning

confidence: 99%

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Maejima

2020

Front. Cardiovasc. Med.

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Three cardiovascular outcome trials of sodium glucose cotransporter 2 (SGLT2) inhibitors, including the EMPA-REG OUTCOME trial, CANVAS Program, and DECLARE TIMI 58 trial, revealed that SGLT2 inhibitors were superior to a matching placebo in reducing cardiovascular events, including mortality and hospitalization for heart failure, in patients with type 2 diabetes. However, the detailed mechanism underlying the beneficial effects that SGLT2 inhibitors exert on cardiovascular diseases remains to be elucidated. We herein review the latest findings of the salutary mechanisms of SGLT2 inhibitors in cardiomyocytes, especially focusing on their mitochondrial function-mediated beneficial effects. The administration of SGLT2 inhibitors leads to the elevation of plasma levels of ketone bodies, which are an efficient energy source in the failing heart, by promoting oxidation of the mitochondrial coenzyme Q couple and enhancing the free energy of cytosolic ATP hydrolysis. SGLT2 inhibitors also promote sodium metabolism-mediated cardioprotective effects. These compounds could reduce the intracellular sodium overload to improve mitochondrial energetics and oxidative defense in the heart through binding with NHE and/or SMIT1. Furthermore, SGLT2 inhibitors could modulate mitochondrial dynamics by regulating the fusion and fission of mitochondria. Together with ongoing large-scale clinical trials to evaluate the efficacy of SGLT2 inhibitors in patients with heart failure, intensive investigations regarding the mechanism through which SGLT2 inhibitors promote the restoration in cases of heart failure would lead to the establishment of these drugs as potent anti-heart failure drugs.

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Section: Future Directionsmentioning

confidence: 99%

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Maejima

2020

Front. Cardiovasc. Med.

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“… 19 In addition, well-functioning mitochondria can buffer [Ca 2+ ]i by active absorption, whereas damaged mitochondria release calcium into the cytoplasm, causing [Ca 2+ ]i overload. 20 Although mitochondrial damage and [Ca 2+ ]i have been shown to promote cardiac microvascular I/R injury, 21 the underlying molecular mechanisms are not known.…”

Section: Introductionmentioning

confidence: 99%

SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

Tan

Mui

Toan

et al. 2020

Molecular Therapy - Nucleic Acids

119

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Despite significant advances in the treatment of myocardial ischemia-reperfusion (I/R) injury, coronary circulation is a so far neglected target of cardioprotection. In this study, we investigated the molecular mechanisms underlying I/R injury to cardiac microcirculation. Using gene delivery, we analyzed microvascular protective effects of sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) on the reperfused heart and examined the role of SERCA in regulating mitochondrial quality control in cardiac microvascular endothelial cells (CMECs). Our data showed that SERCA overexpression attenuates lumen stenosis, inhibits microthrombus formation, reduces inflammation response, and improves endothelium-dependent vascular relaxation. In vitro experiments demonstrated that SERCA overexpression improves endothelial viability, barrier integrity, and cytoskeleton assembly in CMECs. Mitochondrial quality control, including mitochondrial fusion, mitophagy, bioenergetics, and biogenesis, were disrupted by I/R injury but were restored by SERCA overexpression. SERCA overexpression also restored mitochondrial quality control by inhibiting calcium overload, inactivating xanthine oxidase (XO), and reducing intracellular/mitochondrial reactive oxygen species (ROS). Administration of exogenous XO or a calcium channel agonist abolished the protective effects of SERCA overexpression on mitochondrial quality control and offset the beneficial effects of SERCA overexpression after cardiac microvascular I/R injury. These findings indicate that SERCA overexpression may be an effective approach to targeting cardiac microvascular I/R injury by regulating calcium/XO/ROS signaling and preserving mitochondrial quality control.

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“…Along the same line, the SGLT2i empagliflozin was recently found to modulate hyperglycemia-induced microvascular oxidative stress by modulating the p38 MAPK/miR-21 pathway (83). This finding is interesting as recent work has shown that improvement of microvascular function by SGLT2i reduces myocardial inflammation and oxidative stress (84), important features contributing to heart failure development in people with diabetes (85). Although these studies raise significant interest, more research is needed to appraise how new glucose-lowering drugs induce changes of miRNA landscape, and whether these changes are causally implicated in the disease development.…”

Section: Toward Personalized Epigenetic Therapiesmentioning

confidence: 83%

The vascular epigenome in patients with obesity and type 2 diabetes: opportunities for personalized therapies

et al. 2020

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Our genetic background provides limited information on individual risk of developing vascular complications overtime. New biological layers, namely epigenetic modifications, are now emerging as potent regulators of gene expression thus leading to altered transcriptional programs and vascular disease phenotypes. Such epigenetic modifications, defined as changes to the genome that do not involve changes in DNA sequence, are generally induced by environmental factors and poor lifestyle habits. Of note, adverse epigenetic signals acquired during life can be transmitted to the offspring thus leading to premature alterations of the epigenetic and transcriptional landscape eventually leading to early endothelial dysfunction and vascular senescence. Modifications of the epigenome play a pivotal role in the pathophysiology of cardiometabolic disturbances such as obesity and type 2 diabetes. In these patients, changes of DNA methylation and chromatin structure contribute to alter pathways regulating insulin sensitivity, glucose homeostasis, adipogenesis and vascular function. In this perspective, unveiling the ‘epigenetic landscape’ in cardiometabolic patients may help to identify new players implicated in obesity and diabetes-related vascular dysfunction and may pave the way for personalized therapies in this setting. In the present review, we discuss current knowledge of the epigenetic routes implicated in vascular damage and cardiovascular disease in patients with metabolic alterations.

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Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and Restored by Empagliflozin

Abstract: Visual Abstract

Cited by 151 publications

References 59 publications

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

The vascular epigenome in patients with obesity and type 2 diabetes: opportunities for personalized therapies

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