The molecular mechanisms associated with the physiological responses to inflammation and oxidative stress in cardiovascular diseases

Zhazykbayeva, Saltanat; Pabel, Steffen; Mügge, Andreas; Sossalla, Samuel; Hamdani, Nazha

doi:10.1007/s12551-020-00742-0

Cited by 52 publications

(60 citation statements)

References 243 publications

(368 reference statements)

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“…Therefore, in our study, we cannot rule out effects on NHE1 activity. Finally, also other beneficial direct cardiac mechanisms of empagliflozin, i.e., on myofilament function [ 7 ] and on inflammatory and oxidative (paracrine) signaling cascades, have been proposed [ 8 , 27 , 28 ], which may serve as a rationale for further mechanistic studies.…”

Section: Discussionmentioning

confidence: 99%

Long-term effects of empagliflozin on excitation-contraction-coupling in human induced pluripotent stem cell cardiomyocytes

Pabel¹,

Reetz²,

Dybkova

et al. 2020

J Mol Med

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The SGLT2 inhibitor empagliflozin improved cardiovascular outcomes in patients with diabetes. As the cardiac mechanisms remain elusive, we investigated the long-term effects (up to 2 months) of empagliflozin on excitation-contraction (EC)-coupling in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) in a blinded manner. IPSC from 3 donors, differentiated into pure iPSC-CM (4 differentiations), were treated with a clinically relevant concentration of empagliflozin (0.5 μmol/l) or vehicle control. Treatment, data acquisition, and analysis were conducted externally blinded. Epifluorescence microscopy measurements in iPSC-CM showed that empagliflozin has neutral effects on Ca2+ transient amplitude, diastolic Ca2+ levels, Ca2+ transient kinetics, or sarcoplasmic Ca2+ load after 2 weeks or 8 weeks of treatment. Confocal microscopy determining possible effects on proarrhythmogenic diastolic Ca2+ release events showed that in iPSC-CM, Ca2+ spark frequency and leak was not altered after chronic treatment with empagliflozin. Finally, in patch-clamp experiments, empagliflozin did not change action potential duration, amplitude, or resting membrane potential compared with vehicle control after long-term treatment. Next-generation RNA sequencing (NGS) and mapped transcriptome profiles of iPSC-CMs untreated and treated with empagliflozin for 8 weeks showed no differentially expressed EC-coupling genes. In line with NGS data, Western blots indicate that empagliflozin has negligible effects on key EC-coupling proteins. In this blinded study, direct treatment of iPSC-CM with empagliflozin for a clinically relevant duration of 2 months did not influence cardiomyocyte EC-coupling and electrophysiology. Therefore, it is likely that other mechanisms independent of cardiomyocyte EC-coupling are responsible for the beneficial treatment effect of empagliflozin. Key messages This blinded study investigated the clinically relevant long-term effects (up to 2 months) of empagliflozin on cardiomyocyte excitation-contraction (EC)-coupling. Human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) were used to study a human model including a high repetition number of experiments. Empagliflozin has neutral effects on cardiomyocyte Ca2+ transients, sarcoplasmic Ca2+ load, and diastolic sarcoplasmic Ca2+ leak. In patch-clamp experiments, empagliflozin did not change the action potential. Next-generation RNA sequencing, mapped transcriptome profiles, and Western blots of iPSC-CM untreated and treated with empagliflozin showed no differentially expressed EC-coupling candidates.

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Section: Discussionmentioning

confidence: 99%

Long-term effects of empagliflozin on excitation-contraction-coupling in human induced pluripotent stem cell cardiomyocytes

Pabel¹,

Reetz²,

Dybkova

et al. 2020

J Mol Med

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“…Inflammation and oxidative stress play a central role in HF development and progression. Both are associated with increasingly prevalent comorbidities such as chronic kidney disease or metabolic syndrome [ 122 ]. Particularly in HFpEF, inflammation and oxidative stress were shown to cause structural and functional diastolic dysfunction [ 122 , 123 ].…”

Section: Mechanisms Of Sglt2 Inhibitors In Hfmentioning

confidence: 99%

“…Both are associated with increasingly prevalent comorbidities such as chronic kidney disease or metabolic syndrome [ 122 ]. Particularly in HFpEF, inflammation and oxidative stress were shown to cause structural and functional diastolic dysfunction [ 122 , 123 ]. Interestingly, human HFpEF myocardium treated with empagliflozin in vitro exhibited reduced markers of oxidative stress (i.e.…”

Section: Mechanisms Of Sglt2 Inhibitors In Hfmentioning

confidence: 99%

SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled?

Pabel

Hamdani

Luedde

et al. 2021

Curr Heart Fail Rep

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Purpose of review SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms. Recent findings Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Summary Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF.

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“…Nitric oxide radicals are 39 responsible for such effects as decreasing blood pressure and neutrophils phagocytic response. 40 Nitrosative stress plays a role in the development and pathogenesis of many disease conditions like heart disease, congestive heart failure, 41,42 hypertension, cerebrovascular accidents, and diabetic complications. 43 The deleterious effect of NO radicals lies in their ability to react with superoxide anion to produce highly reactive hydroxyl radical ( .…”

Section: Reducing Power Determinationmentioning

confidence: 99%

Antioxidative and Free Radical Scavenging Properties of Ethyl Acetate Fractions of Persea americana Seed and Bryophyllum pinnatum Leaf

2021

TJNPR

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Medicinal plants are known for their importance in the management of ailments and as sources of nutrients for growth and nutritional balance. 1 Plants" medicinal properties are attributable to their primary and secondary metabolites which exert their medicinal activity through antioxidative effects, free radicals scavenging, induction of enzymes, and activation of important biochemical pathways. 2 Free radicals are important in cellular phagocytosis, respiration, and mitochondrial energy generation. 3 Oxidative stress arises from an imbalance between stressors and stress-reducing factors. A shift of this delicate balance in favor of stressors such as the increase in reactive oxygen species, reduction in the concentration of antioxidants, and regenerating enzymes result in a distortion in important macromolecules such as lipids, carbohydrates, proteins, and nucleic acids. 4 Free radicals play a prominent role in the etiology of diseases such as diabetes mellitus, gastric ulcer, Alzheimer"s disease, rheumatoid arthritis, respiratory diseases (asthma), cataract development e.t.c. 5,6 Recently, researchers have focused on harnessing plants and plant products in crude or purified forms as a remedy in

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The molecular mechanisms associated with the physiological responses to inflammation and oxidative stress in cardiovascular diseases

Cited by 52 publications

References 243 publications

Long-term effects of empagliflozin on excitation-contraction-coupling in human induced pluripotent stem cell cardiomyocytes

Long-term effects of empagliflozin on excitation-contraction-coupling in human induced pluripotent stem cell cardiomyocytes

SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled?

Antioxidative and Free Radical Scavenging Properties of Ethyl Acetate Fractions of Persea americana Seed and Bryophyllum pinnatum Leaf

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