Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

Circulation, Journal Year: 2022, Volume and Issue: 146(18), P. 1383 - 1405

Published: Oct. 31, 2022

SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression cardiomyopathy nephropathy, which is characterized by reduction in oxidative endoplasmic reticulum stress, restoration mitochondrial health enhanced biogenesis, decrease proinflammatory profibrotic pathways, preservation cellular organ integrity viability. A substantial body evidence indicates that this characteristic responses can be explained action to promote housekeeping enhancing autophagic flux, an effect may related these drugs simultaneous upregulation nutrient deprivation signaling downregulation surplus signaling, as manifested increase expression activity AMPK (adenosine monophosphate-activated protein kinase), SIRT1 (sirtuin 1), SIRT3 3), SIRT6 6), PGC1-α (peroxisome proliferator-activated receptor γ coactivator 1-α) decreased activation mTOR (mammalian target rapamycin). The cardioprotective renoprotective effects abolished specific inhibition or knockdown autophagy, AMPK, sirtuins. In clinical setting, differentially increased proteins identified proteomics analyses blood collected randomized trials consistent with findings. Clinical studies have also shown gluconeogenesis, ketogenesis, erythrocytosis reduce uricemia, hallmarks principal statistical mediators ability risk heart failure serious renal events. augment flux seen isolated cells tissues do not express are exposed changes environmental glucose ketones bind directly sirtuins mTOR. Changes cardiovascular physiology metabolism cannot explain either experimentally clinically. direct molecular concept acts sensor, thus, its causes attendant cytoprotective effects, sirtuins, flux.

Language: Английский

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SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits

Cardiovascular Research, Journal Year: 2024, Volume and Issue: 120(5), P. 443 - 460

Published: March 8, 2024

Abstract An increasing number of individuals are at high risk type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule human nephrons to regulate glucose reabsorption inhibition by gliflozins represents cornerstone contemporary T2D HF management. Herein, we aim provide an updated overview pleiotropy gliflozins, mechanistic insights delineate related (CV) benefits. By discussing evidence obtained preclinical models landmark randomized controlled trials, move from bench bedside across broad spectrum cardio- cerebrovascular diseases. With trials confirming a reduction major adverse CV events (MACE; composite endpoint death, non-fatal myocardial infarction, stroke), SGLT2 inhibitors strongly mitigate for hospitalization diabetics non-diabetics alike while conferring renoprotection specific patient populations. Along four pathophysiological axes (i.e. systemic, vascular, cardiac, renal levels), into key mechanisms that may underlie their beneficial effects, gliflozins’ role modulation inflammation, oxidative stress, cellular energy metabolism, housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, hyperuricaemia, collectively contributing pleiotropic effects. Finally, evolving data setting diseases arrhythmias presented potential implications future research clinical practice comprehensively reviewed.

Language: Английский

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The Janus face of mitophagy in myocardial ischemia/reperfusion injury and recovery

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 173, P. 116337 - 116337

Published: Feb. 28, 2024

In myocardial ischemia/reperfusion injury (MIRI), moderate mitophagy is a protective or adaptive mechanism because of clearing defective mitochondria accumulates during MIRI. However, excessive lead to an increase in and ultimately exacerbate MIRI by causing overproduction uncontrolled production mitochondria. Phosphatase tensin homolog (PTEN)-induced kinase 1 (Pink1), Parkin, FUN14 domain containing (FUNDC1) B-cell leukemia/lymphoma 2 (BCL-2)/adenovirus E1B19KD interaction protein 3 (BNIP3) are the main mechanistic regulators Pink1 Parkin mitochondrial surface proteins involved ubiquitin-dependent pathway, while BNIP3 FUNDC1 receptor non-ubiquitin-dependent which play crucial role maintaining homeostasis quality. These can induce inhibit protect against but may also trigger insufficient mitophagy, thereby worsening condition. Understanding actions these provide valuable insights into pathological mechanisms underlying development. Based on above background, this article reviews through Pink1/Parkin pathway mediated led BNIP3, as well related drug treatment, aim effective strategies for prevention treatment

Language: Английский

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Mitochondrial quality control in human health and disease

Military Medical Research, Journal Year: 2024, Volume and Issue: 11(1)

Published: May 29, 2024

Abstract Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable vital life processes such cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key like biogenesis, dynamics, mitophagy, which have garnered increasing attention from researchers unveil specific molecular mechanisms. this review, we present comprehensive summary of primary mechanisms functions regulators involved major components MQC. Furthermore, critical regulated by MQC its diverse roles progression systemic diseases been described detail. We discuss agonists antagonists targeting MQC, aiming explore potential therapeutic research prospects enhancing stabilize function.

Language: Английский

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Cardiovascular benefits of SGLT2 inhibitors and GLP-1 receptor agonists through effects on mitochondrial function and oxidative stress

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 213, P. 19 - 35

Published: Jan. 13, 2024

Overloaded glucose levels in several metabolic diseases such as type 2 diabetes (T2D) can lead to mitochondrial dysfunction and enhanced production of reactive oxygen species (ROS). Oxidative stress altered homeostasis, particularly the cardiovascular system, contribute development chronic comorbidities diabetes. Diabetes-associated hyperglycemia dyslipidemia directly damage vascular vessels coronary artery disease or stroke, indirectly other organs kidney dysfunction, known diabetic nephropathy. The new treatments include Na+-glucose cotransporter inhibitors (iSGLT2) glucagon-like 1 peptide receptor agonists (GLP-1RA), among others. iSGLT2 are oral anti-diabetic drugs, whereas GLP-1RA preferably administered through subcutaneous injection, even though formulations have recently become available. Both therapies improve both carbohydrate lipid metabolism, well cardiorenal outcomes patients. In this review, we present an overview current knowledge on relationship between oxidative stress, therapeutic benefits GLP-1RA. We explore benefits, limits common features remark how interesting target prevention obesity, T2D diseases, emphasize lack a complete understanding underlying mechanism action.

Language: Английский

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Ginsenoside Rb1 ameliorates heart failure through DUSP-1-TMBIM-6-mediated mitochondrial quality control and gut flora interactions

Phytomedicine, Journal Year: 2024, Volume and Issue: 132, P. 155880 - 155880

Published: July 20, 2024

Language: Английский

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Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway

Pharmacological Research, Journal Year: 2024, Volume and Issue: 200, P. 107057 - 107057

Published: Jan. 11, 2024

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial and DCM; however, its effects on mitophagy remain unexplored. The present study aimed to assess the beneficial of nicorandil DCM underlying mechanisms. Cardiac perfusion was assessed using a lectin assay, while via mt-Keima transfection transmission electron microscopy. Ferroptosis examined mRNA sequencing, fluorescence staining, western blotting. localization Parkin, ACSL4, AMPK determined immunofluorescence staining. Following long-term diabetes, treatment improved function remodeling by alleviating injuries, as evidenced structural integrity. mRNA-sequencing biochemical analyses showed that occurred Pink1/Parkin-dependent suppressed cells after diabetes. Nicorandil mitochondria-associated promoting mitophagy. Moreover, increased phosphorylation level AMPKα1 promoted translocation, which further inhibited translocation ACSL4 ultimately ferroptosis. Importantly, overexpression mitochondria-localized (mitoAα1) shared similar benefits with mitophagy, cardiovascular protection injury. In conclusion, demonstrated therapeutic revealed AMPK-Parkin-ACSL4 signaling pathway mediates development dysfunction.

Language: Английский

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Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options

Biomedicines, Journal Year: 2022, Volume and Issue: 10(9), P. 2274 - 2274

Published: Sept. 14, 2022

Diabetic patients are frequently affected by coronary microvascular dysfunction (CMD), a condition consisting of combination altered vasomotion and long-term structural change to arterioles leading impaired regulation blood flow in response changing cardiomyocyte oxygen requirements. The pathogenesis this complication is complex not completely known, involving several alterations among which hyperglycemia insulin resistance play particularly central roles oxidative stress, inflammatory activation barrier function endothelium. CMD significantly contributes cardiac events such as angina or infarction without obstructive artery disease, well heart failure, especially the phenotype associated with preserved ejection fraction, greatly impact cardiovascular (CV) prognosis. To date, no treatments specifically target vascular damage, but recent experimental studies some clinical investigations have produced data favor potential beneficial effects on micro vessels caused two classes glucose-lowering drugs: glucagon-like peptide 1 (GLP-1)-based therapy inhibitors sodium-glucose cotransporter-2 (SGLT2). purpose review describe pathophysiological mechanisms, manifestations particular reference diabetes, summarize protective antidiabetic drugs myocardial compartment.

Language: Английский

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ß-tubulin contributes to Tongyang Huoxue decoction-induced protection against hypoxia/reoxygenation-induced injury of sinoatrial node cells through SIRT1-mediated regulation of mitochondrial quality surveillance

Phytomedicine, Journal Year: 2022, Volume and Issue: 108, P. 154502 - 154502

Published: Oct. 13, 2022

Language: Английский

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Empagliflozin attenuates trastuzumab-induced cardiotoxicity through suppression of DNA damage and ferroptosis

Life Sciences, Journal Year: 2022, Volume and Issue: 312, P. 121207 - 121207

Published: Nov. 17, 2022

Language: Английский

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