Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

Nature Reviews Cardiology, Journal Year: 2020, Volume and Issue: 17(6), P. 341 - 359

Published: Feb. 3, 2020

Language: Английский

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Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence

Nature Reviews Cardiology, Journal Year: 2020, Volume and Issue: 17(9), P. 585 - 607

Published: Feb. 20, 2020

Language: Английский

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Targeting integrin pathways: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 2, 2023

Abstract Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical mechanical signals between cells their environment a wide range of states health diseases. Integrin functions dependable on delicate balance active inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, trafficking. Due to exposure cell surface sensitivity molecular blockade, integrins have been investigated pharmacological targets for nearly 40 years, but given complexity sometimes opposite characteristics, targeting integrin therapeutics has challenge. To date, only seven drugs successfully marketed, abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, carotegrast. Currently, there approximately 90 kinds integrin-based therapeutic or imaging agents clinical studies, small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, agents, etc. A serious lesson from past drug discovery research efforts is successes rely both deep understanding integrin-regulatory mechanisms unmet needs. Herein, we provide systematic complete review all family members integrin-mediated downstream signal transduction highlight ongoing develop new therapies/diagnoses bench clinic. In addition, further discuss trend development, how improve success rate trials therapies, key points research, basic translational research.

Language: Английский

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Cellular and molecular pathobiology of heart failure with preserved ejection fraction

Nature Reviews Cardiology, Journal Year: 2021, Volume and Issue: 18(6), P. 400 - 423

Published: Jan. 11, 2021

Language: Английский

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Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications

Physiological Reviews, Journal Year: 2021, Volume and Issue: 101(4), P. 1745 - 1807

Published: May 5, 2021

The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to rapidly increased overweight obesity. To this point, epidemiological, clinical, experimental evidence supports existence unique disease entity termed "obesity cardiomyopathy," which develops independent hypertension, coronary disease, other diseases. Our contemporary review evaluates for pathological condition, examines putative responsible mechanisms, discusses therapeutic options disorder. Clinical findings have consolidated presence left ventricular dysfunction Experimental investigations uncovered pathophysiological changes myocardial structure function genetically predisposed diet-induced Indeed, consolidates wide array cellular molecular mechanisms underlying etiology obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover free fatty acids, lipotoxicity, amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, fibrosis, dampened flow reserve, microvascular (microangiopathy), endothelial impairment. Given important role risk failure, that with preserved systolic recent rises COVID-19-associated cardiovascular mortality, should provide compelling cardiomyopathy, various comorbid conditions, offer new insights into potential approaches (pharmacological lifestyle modification) clinical management cardiomyopathy.

Language: Английский

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Cardiomyopathy in obesity, insulin resistance and diabetes

The Journal of Physiology, Journal Year: 2019, Volume and Issue: 598(14), P. 2977 - 2993

Published: March 14, 2019

Abstract The prevalence of obesity, insulin resistance and diabetes is increasing rapidly. Most patients with these disorders have hypertriglyceridaemia increased plasma levels fatty acids, which are taken up stored in lipid droplets the heart. Intramyocardial lipids that exceed capacity for storage oxidation can be lipotoxic induce non‐ischaemic non‐hypertensive cardiomyopathy, termed diabetic or cardiomyopathy. clinical features cardiomyopathy cardiac hypertrophy diastolic dysfunction, lead to heart failure, especially failure preserved ejection fraction. Although pathogenesis multifactorial, dyslipidaemia intramyocardial accumulation key pathological features, triggering cellular signalling modifications proteins via generation toxic metabolic intermediates. studies shown no beneficial effect anti‐diabetic agents statins on outcomes without atherosclerotic diseases, indicating importance identifying underlying mechanisms early interventions Here, we summarize molecular a special emphasis lipotoxicity, discuss role peroxisome proliferator‐activated receptor α dysregulated acid metabolism as potential therapeutic targets.

Language: Английский

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Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy

Circulation, Journal Year: 2020, Volume and Issue: 141(21), P. 1704 - 1719

Published: March 18, 2020

Pressure overload-induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter which remains major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving heart's workload after onset failure. Thus, more pathogenesis-, stage-, cell type-specific treatment strategies require refined dissection entire progression at cellular molecular levels.By analyzing transcriptomes 11,492 single cells identifying types, including both cardiomyocytes noncardiomyocytes, on basis their signatures, different stages during pressure in mouse model, we characterized spatiotemporal interplay among tested potential pharmacological to retard its vivo.We illustrated dynamics all cardiomyocytes, endothelial cells, fibroblasts, macrophages, as well those respective subtypes, disease. Cellular crosstalk analysis revealed stagewise utilization specific noncardiomyocytes deterioration function. Specifically, macrophage activation subtype switching, key event middle-stage hypertrophy, was successfully targeted by Dapagliflozin, sodium glucose cotransporter 2 inhibitor, clinical trials for patients TD139 Arglabin, two anti-inflammatory agents new diseases, preserve function attenuate fibrosis. Similar patterns were also observed human patient samples hypertrophic cardiomyopathy failure.Together, our study not only dynamically changing type but shed light type- stage-specific intervention diseases.

Language: Английский

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The role of cellular senescence in cardiac disease: basic biology and clinical relevance

Nature Reviews Cardiology, Journal Year: 2021, Volume and Issue: 19(4), P. 250 - 264

Published: Oct. 19, 2021

Language: Английский

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Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: May 24, 2021

Biophysical cues, such as mechanical properties, play a critical role in tissue growth and homeostasis. During organ development injury repair, compressive tensional forces generated by cell-extracellular matrix or cell-cell interaction are key factors for cell fate determination. In the vascular system, hemodynamic forces, shear stress, cyclic stretch modulate phenotypes susceptibility to atherosclerosis. Despite that emerging efforts have been made investigate how mechanotransduction is involved tuning functions various contexts, regulatory mechanisms remain largely unknown. One of challenges understand signaling cascades transmit cues from plasma membrane cytoplasm then nuclei generate mechanoresponsive transcriptomes. YAP its homolog TAZ, Hippo pathway effectors, identified mechanotransducers sense stimuli relay signals control transcriptional programs proliferation, differentiation, transformation. However, upstream mechanosensors YAP/TAZ downstream transcriptome responses following activation repression not well characterized. Moreover, mechanoregulation literature highly context-dependent. this review, we summarize biomechanical microenvironment provide an update on roles physiological pathological conditions.

Language: Английский

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Cardiac Resident Macrophages Prevent Fibrosis and Stimulate Angiogenesis

Circulation Research, Journal Year: 2021, Volume and Issue: 129(12), P. 1086 - 1101

Published: Oct. 14, 2021

The initial hypertrophy response to cardiac pressure overload is considered compensatory, but with sustained stress, it eventually leads heart failure. Recently, a role for recruited macrophages in determining the transition from compensated decompensated has been established. However, whether resident immune cells influence early phase of development not established.To assess induced by transverse aortic constriction (TAC).We performed cytometry time-of-flight determine identity and abundance at 1 4 weeks after TAC. We observed substantial increase week then conducted Cite-Seq single-cell RNA sequencing isolated sham 6 TAC hearts. identified 12 clusters monocytes macrophages, categorized as either or that showed remarkable changes their between conditions. To hypertrophic stimulus, we used blocking antibody against macrophage colony-stimulating factor receptor (CD115). As CD115 initially depletes all allowed replenishment before performing This preferential depletion resulted enhanced fibrosis blunted angiogenesis Macrophage CCR2 (C-C chemokine type 2) knockout mice aggravated was primarily caused recruitment monocyte-derived macrophages. Finally, these events lead depressed function fibrosis, despite complete restoration cells.Cardiac are heterogeneous population key roles stimulating inhibiting overload.

Language: Английский

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