Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Ноя. 20, 2023

Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays prominent role in cardiovascular diseases. From research history milestone events related to hypoxia development diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal spatial perspectives, encompassing occurrence progression (gradual decline concentration), acute chronic manifestations hypoxia, geographical characteristics (natural selection at high altitudes). Furthermore, signaling pathways are associated with natural rhythms, such as diurnal hibernation processes. In addition innate selection, it has been found epigenetics, postnatal factor, profoundly influences hypoxic response within system. Within this intricate process, interactions between different tissues organs system other systems context have established. Thus, time summarize construct multi-level regulatory framework mechanisms diseases for developing more therapeutic targets make reasonable advancements clinical research, including FDA-approved drugs ongoing trials, guide future practice field

Язык: Английский

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SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits

Cardiovascular Research, Год журнала: 2024, Номер 120(5), С. 443 - 460

Опубликована: Март 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.

Язык: Английский

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SGLT2 Inhibitors, Functional Capacity, and Quality of Life in Patients With Heart Failure

JAMA Network Open, Год журнала: 2024, Номер 7(4), С. e245135 - e245135

Опубликована: Апрель 4, 2024

Importance The associations of sodium glucose cotransporter-2 inhibitors (SGLT2is) with reduction in mortality and hospitalization rates patients heart failure (HF) are well established. However, their association improving functional capacity quality life (QOL) has been variably studied less reported. Objective To provide evidence on the extent to which SGLT2is associated improvement objective measures QOL living HF. Data Sources MEDLINE, EMBASE, Cochrane databases were systematically searched for relevant articles July 31, 2023. Study Selection Randomized, placebo-controlled clinical trials reporting effect SGLT2i outcomes exercise (peak oxygen consumption [peak VO 2 ] or 6-minute walk distance [6MWD]) and/or using validated questionnaires HF included. Extraction Synthesis extracted by authors following Preferred Reporting Items Systematic Reviews Meta-Analyses 2020 guidelines, a meta-analysis restricted maximum likelihood random-effects model was conducted. Main Outcomes Measures interest included changes peak , 6MWD, Kansas City Cardiomyopathy Questionnaire-12 total symptom score (KCCQ-TSS), summary (KCCQ-CSS), overall (KCCQ-OSS). Results In this 17 studies, 23 523 (mean [range] age, 69 [60-75] years) followed over period ranging from 12 52 weeks. Four studies as an outcome, 7 10 reported KCCQ scores. Mean (SD) left ventricular ejection fraction 43.5% (12.4%). Compared controls, receiving treatment experienced significant increases difference [MD], 1.61 mL/kg/min; 95% CI, 0.59-2.63 P = .002) 6MWD (MD, 13.09 m; 1.20-24.97 .03). use increased KCCQ-TSS 2.28 points; 1.74-2.81 < .001), KCCQ-CSS 2.14 1.53-2.74 KCCQ-OSS 1.90 1.41-2.39 .001) Subgroup analysis meta-regression demonstrated almost all improvements consistent across fraction, sex, presence diabetes. Conclusions Relevance These findings suggest that addition known outcomes, is patients’ everyday lives measured assessments maximal questionnaires, regardless sex fraction.

Язык: Английский

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Use of SGLT2 Inhibitors vs GLP-1 RAs and Anemia in Patients With Diabetes and CKD

JAMA Network Open, Год журнала: 2024, Номер 7(3), С. e240946 - e240946

Опубликована: Март 4, 2024

Importance Sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with lower anemia risk, based on findings from post hoc analyses of the CREDENCE and DAPA-CKD trials; however, effectiveness SGLT2 in a more generalizable type diabetes (T2D) chronic kidney disease (CKD) population, active comparisons pertinent to current practice, is unknown. Objective To evaluate compare incidence between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among patients T2D CKD stages 1 3. Design, Setting, Participants This retrospective cohort study used target trial emulation an expanded framework. The was conducted adults initiating or GLP-1 RAs January 1, 2016, December 31, 2021, follow-up until 2022. at Chang Gung Medical Foundation, largest multi-institutional hospital system Taiwan. Exposures Initiation RAs. Main Outcomes Measures primary outcome composite outcomes, including event occurrence (hemoglobin level <12-13 g/dL International Statistical Classification Diseases, Tenth Revision, Clinical Modification diagnosis codes) treatment initiation. Changes hematological parameters, hemoglobin level, hematocrit red blood cell count, were evaluated during period for as long 3 years. Results included total 13 799 CKD, (12 331 patients; mean [SD] age, 62.4 [12.3] years; 7548 [61.2%] male) (1468 61.5 [13.3] 900 [61.3%] male). After median 2.5 years, receiving had outcomes (hazard ratio [HR], 0.81; 95% CI, 0.73-0.90) compared those events (HR, 0.79; 0.71-0.87) but not rate initiation 0.99; 0.83-1.19). parameters throughout 3-year supported analyses. Conclusions Relevance In this emulation, decreased risk especially occurrences. may be considered adjunct therapy reduce CKD.

Язык: Английский

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Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia

American Journal of Nephrology, Год журнала: 2023, Номер 55(2), С. 255 - 259

Опубликована: Май 16, 2023

Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, advanced chronic kidney disease, HIF-PHD can death, heart failure, thrombotic events a greater extent than that indicating there compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) reduce major they hemoglobin, effect related erythropoietin expansion red blood cell mass. SGLT2 hemoglobin by ≈0.6–0.7 g/dL, resulting alleviation many patients. The magnitude this seen low-to-medium doses inhibitors, it apparent disease. Interestingly, act interfering hydroxylases degrade both HIF-1α HIF-2α, thus enhancing isoforms. HIF-2α physiological stimulus production erythropoietin, upregulation may be unnecessary ancillary property which adverse cardiac vascular consequences. In contrast, selectively while downregulating HIF-1α, distinctive profile contribute their cardiorenal benefits. Intriguingly, liver likely important site increased production, recapitulating fetal phenotype. These observations suggest use should seriously evaluated therapeutic approach treat renal anemia, yielding less other options.

Язык: Английский

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Slowing the Progression of Diabetic Kidney Disease

Cells, Год журнала: 2023, Номер 12(15), С. 1975 - 1975

Опубликована: Июль 31, 2023

Diabetes is the most frequent cause of kidney disease that progresses to end-stage renal worldwide, and diabetic significantly related unfavorable cardiovascular outcomes. Since 1990s, specific therapies have emerged been approved slow progression disease, namely, renin–angiotensin–aldosterone system blockers (including angiotensin-converting enzyme inhibitors (ACEi) angiotensin receptor (ARBs), non-steroidal mineralocorticoid antagonist (NS-MRA), finerenone, sodium–glucose cotransporter-2 (SGLT2) inhibitors). Mechanistically, these different classes agents bring anti-inflammatory, anti-fibrotic, complementary hemodynamic effects patients with such they additive benefits on slowing progression. Within coming year, there will be data outcomes using glucagon-like peptide-1 agonist, semaglutide. All aforementioned medications also shown improve Thus, all three (maximally dosed ACEi or ARB, low-dose SGLT-2 inhibitors, NS-MRA, finerenone) form “pillars therapy” that, when used together, maximally Ongoing studies aim expand pillars additional potentially normalize decline in function reduce associated mortality.

Язык: Английский

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Sodium–glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond

Basic Research in Cardiology, Год журнала: 2024, Номер unknown

Опубликована: Июнь 27, 2024

Abstract Sodium–glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic direct cardioprotective nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted use in two frequently intertwined conditions, heart failure chronic kidney disease. Their unique mechanism action makes SGLT2i an attractive option also lower the rate cardiac events improve overall survival oncological patients with preexisting cardiovascular risk and/or candidate receive cardiotoxic therapies. This review will cover biological foundations clinical evidence modulating myocardial function metabolism, focus on possible as agents cardio-oncology settings. Furthermore, we explore recently emerged hematopoiesis immune system, carrying potential attenuating tumor growth chemotherapy-induced cytopenias.

Язык: Английский

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Effects of dapagliflozin and dapagliflozin-saxagliptin on erythropoiesis, iron and inflammation markers in patients with type 2 diabetes and chronic kidney disease: data from the DELIGHT trial

Cardiovascular Diabetology, Год журнала: 2023, Номер 22(1)

Опубликована: Ноя. 28, 2023

Abstract Background This post-hoc analysis of the DELIGHT trial assessed effects SGLT2 inhibitor dapagliflozin on iron metabolism and markers inflammation. Methods Patients with type 2 diabetes albuminuria were randomized to dapagliflozin, saxagliptin, or placebo. We measured hemoglobin, (serum iron, transferrin saturation, ferritin), plasma erythropoietin, inflammatory (urinary MCP-1 urinary/serum IL-6) at baseline week 24. Results 360/461 (78.1%) participants had available biosamples. Dapagliflozin dapagliflozin-saxagliptin, compared placebo, increased hemoglobin by 5.7 g/L (95%CI 4.0, 7.3; p < 0.001) 4.4 (2.7, 6.0; reduced ferritin 18.6% (8.7, 27.5; 18.4% 27.1; 0.001), respectively. urinary MCP-1/Cr 29.0% (14.6, 41.0; IL-6/Cr 26.6% (9.1, 40.7; = 0.005) no changes in other markers. Conclusions inflammation, suggesting potentially important Trial registration ClinicalTrials.gov NCT02547935.

Язык: Английский

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Anti-Inflammation and Anti-Oxidation: The Key to Unlocking the Cardiovascular Potential of SGLT2 Inhibitors and GLP1 Receptor Agonists

Antioxidants, Год журнала: 2023, Номер 13(1), С. 16 - 16

Опубликована: Дек. 20, 2023

Type 2 diabetes mellitus (T2DM) is a prevalent and complex metabolic disorder associated with various complications, including cardiovascular diseases. Sodium-glucose co-transporter inhibitors (SGLT2i) glucagon-like peptide 1 receptor agonists (GLP1-RA) have emerged as novel therapeutic agents for T2DM, primarily aiming to reduce blood glucose levels. However, recent investigations unveiled their multifaceted effects, extending beyond glucose-lowering effect. SGLT2i operate by inhibiting the SGLT2 in kidneys, facilitating excretion of through urine, leading reduced levels, while GLP1-RA mimic action GLP1 hormone, stimulating glucose-dependent insulin secretion from pancreatic islets. Both shown remarkable benefits reducing major events patients without T2DM. This comprehensive review explores expanding horizons improving health. It delves into latest research, highlighting effects these drugs on heart physiology metabolism. By elucidating diverse mechanisms emerging evidence, this aims recapitulate potential options health traditional role managing

Язык: Английский

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The Role of SGLT1 in Atrial Fibrillation and Its Relationship with Endothelial-Mesenchymal Transition

Biochemical and Biophysical Research Communications, Год журнала: 2025, Номер 748, С. 151338 - 151338

Опубликована: Янв. 14, 2025

Язык: Английский

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