Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease

Physiological Reviews, Journal Year: 2019, Volume and Issue: 99(4), P. 1765 - 1817

Published: July 31, 2019

Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including receptor-mediated apoptosis, necrosis (necroptosis), mitochondrial-mediated necrosis, autophagy-dependent death, ferroptosis, pyroptosis, parthanatos, and immunogenic death. This is followed by a dissection roles these major cardiac syndromes: myocardial infarction heart failure. The most important conclusion relevant to disease that forms cardiomyocyte play both with reperfusion (ischemia/reperfusion) While role for apoptosis ischemia/reperfusion cannot be excluded, through receptor mitochondrial pathways, are critical. Ferroptosis parthanatos also likely ischemia/reperfusion, although it unclear if entities functioning as independent or amplification mechanisms necrotic Pyroptosis may contribute injury, but potentially effects non-cardiomyocytes. Cardiomyocyte loss an component pathogenesis failure mediated signaling. Roles remain defined merit study this era immune checkpoint cancer therapy. Biology-based approaches inhibit various syndromes discussed.

Language: Английский

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The NLRP3 inflammasome in acute myocardial infarction

Nature Reviews Cardiology, Journal Year: 2017, Volume and Issue: 15(4), P. 203 - 214

Published: Nov. 16, 2017

Language: Английский

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The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

Circulation Research, Journal Year: 2019, Volume and Issue: 125(1), P. 117 - 146

Published: June 20, 2019

The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also facilitating force transmission, and transducing key signals to cardiomyocytes, vascular cells, interstitial cells. Changes the profile biochemistry of may be critically implicated pathogenesis both heart failure with reduced ejection fraction preserved fraction. patterns molecular biochemical alterations failing hearts are dependent on type underlying injury. Pressure overload triggers early activation matrix-synthetic program fibroblasts, inducing myofibroblast conversion, stimulating synthesis matricellular proteins. Expansion increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, cells immune activated through mechanosensitive pathways or neurohumoral mediators play critical fibroblast secretion cytokines growth factors. Sustained pressure leads dilative remodeling systolic dysfunction that mediated changes protease/antiprotease balance. On other hand, ischemic injury causes dynamic contribute regulation inflammation repair mediate adverse remodeling. In pathophysiologic conditions, such as volume overload, diabetes mellitus, obesity, cell biological effectors mediating poorly understood links between primary insult matrix environment unknown. This review article discusses macromolecules failure, focusing proteins (such fibrillar nonfibrillar collagens), specialized injury-associated fibronectin proteins). Understanding identify therapeutic targets reduce geometric remodeling, attenuate cardiomyocyte dysfunction, even promote regeneration.

Language: Английский

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Obesity, Hypertension, and Cardiac Dysfunction

Circulation Research, Journal Year: 2020, Volume and Issue: 126(6), P. 789 - 806

Published: March 12, 2020

Obesity and hypertension, which often coexist, are major risk factors for heart failure characterized by chronic, low-grade inflammation, promotes adverse cardiac remodeling. While macrophages play a key role in remodeling, dysregulation of macrophage polarization between the proinflammatory M1 anti-inflammatory M2 phenotypes excessive inflammation injury. Metabolic shifting glycolysis mitochondrial oxidative phosphorylation has been implicated polarization. primarily rely on glycolysis, whereas tricarboxylic acid cycle phosphorylation; thus, that affect metabolism may disrupt M1/M2 homeostasis exacerbate inflammation. The mechanisms obesity hypertension synergistically induce metabolic dysfunction, particularly during not fully understood. We propose via directly target metabolism, including changes circulating glucose fatty substrates, lipotoxicity, tissue hypoxia. discuss canonical novel roles obesity-hypertension-induced injury, diastolic dysfunction impaired calcium handling. Finally, we current status potential therapies to failure, antidiabetic therapies, immunometabolic agents.

Language: Английский

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Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy

Circulation Research, Journal Year: 2020, Volume and Issue: 127(1), P. 51 - 72

Published: June 18, 2020

Atrial fibrillation (AF) is a highly prevalent arrhythmia, with substantial associated morbidity and mortality. There have been significant management advances over the past 2 decades, but burden of disease continues to increase there certainly plenty room for improvement in treatment options. A potential key therapeutic innovation better understanding underlying fundamental mechanisms. This article reviews recent molecular basis AF, particular emphasis on relating these new insights opportunities clinical translation. We first review evidence basic electrophysiological mechanisms characteristics AF. then discuss control factors leading some principal determinants, including abnormalities impulse conduction (such as tissue fibrosis other extra-cardiomyocyte alterations, connexin dysregulation Na

Language: Английский

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Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

Cardiovascular Drugs and Therapy, Journal Year: 2020, Volume and Issue: 34(6), P. 849 - 863

Published: Sept. 9, 2020

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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Therapeutic Potential of Centella asiatica and Its Triterpenes: A Review

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: Sept. 4, 2020

Centella asiatica (also known as (L.) Urb. or Gotu kola) is a traditional Chinese medicine with extensive medicinal value, which mainly used in Southeast Asian countries. This study aimed to summarize the effects of C. and its main components on neurological diseases, endocrine skin cardiovascular gastrointestinal immune gynecological well potential molecular mechanisms, pathological mechanism these diseases based changes at level. The results showed that triterpenoids had beneficial were confirmed through clinical studies. They exhibited anti-inflammatory, anti-oxidative stress, anti-apoptotic effects, improvement mitochondrial function. However, further studies are urgently required due low level evidence lack patients.

Language: Английский

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Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation

Circulation Research, Journal Year: 2020, Volume and Issue: 127(8), P. 1036 - 1055

Published: July 30, 2020

Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF generally believed to occur when postoperative triggers act on preexisting vulnerable substrate, but the underlying cellular molecular mechanisms are largely unknown.To identify in right samples from patients without history undergoing open-heart surgery.Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) [Ca2+]i-recordings cardiomyocytes, along with protein-expression levels tissue homogenates were assessed 265 POAF. No indices electrical, profibrotic, connexin remodeling noted POAF, Ca2+-transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca2+-release events L-type Ca2+-current alternans occurred more frequently. CaMKII (Ca2+/calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation RyR2 (ryanodine-receptor channel type-2), single-channel open-probability significantly increased SR Ca2+-content unchanged despite greater Ca2+-leak, trend towards Ca2+-ATPase activity. Patients also showed stronger expression activated components NLRP3 (NACHT, LRR, PYD domains-containing protein-3)-inflammasome system whole-tissue cardiomyocytes. Acute application interleukin-1β caused NLRP3-signaling activation RyR2/phospholamban hyperphosphorylation an immortalized mouse cardiomyocyte cell-line (HL-1-cardiomyocytes) enhanced both cardiomyocytes HL-1-cardiomyocytes. Computational modeling that dysfunction Ca2+-uptake sufficient reproduce Ca2+-handling phenotype indicated risk proarrhythmic delayed afterdepolarizations subjects response interleukin-1β.Preexisting abnormalities NLRP3-inflammasome/CaMKII signaling evident who subsequently develop These substrates sensitize Ca2+-releases arrhythmogenic afterdepolarizations, particularly upon exposure inflammatory mediators. Our data reveal potential substrate for this important clinical problem.

Language: Английский

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Targeting the NLRP3 inflammasome in cardiovascular diseases

Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 236, P. 108053 - 108053

Published: Dec. 11, 2021

Language: Английский

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