Functional Effects and Molecular Mechanisms of Subtype-Selective ERα and ERβ Agonists in the Cardiovascular System

2007 ◽  
pp. 87-106
Author(s):  
P. A. Arias-Loza ◽  
V. Jazbutyte ◽  
K.-H. Fritzemeier ◽  
C. Hegele-Hartung ◽  
L. Neyses ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Molecular Mechanisms ◽  
Subtype Selective

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

2020 ◽  
Vol 134 (17) ◽  
pp. 2243-2262
Author(s):  
Danlin Liu ◽  
Gavin Richardson ◽  
Fehmi M. Benli ◽  
Catherine Park ◽  
João V. de Souza ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiovascular System ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Cardiovascular Research ◽  
Inflammatory Processes ◽  
Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

Molecular Mechanisms of the Inhibitory Effects of Bupivacaine, Levobupivacaine, and Ropivacaine on Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channels in the Cardiovascular System

2004 ◽  
Vol 101 (2) ◽  
pp. 390-398 ◽  
Author(s):  
Takashi Kawano ◽  
Shuzo Oshita ◽  
Akira Takahashi ◽  
Yasuo Tsutsumi ◽  
Yoshinobu Tomiyama ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Adenosine Triphosphate ◽  
Local Anesthetics ◽  
Molecular Mechanisms ◽  
Transmembrane Domain ◽  
Katp Channels ◽  
Inhibitory Effect ◽  
Amino Acid Residues ◽  
Sulfonylurea Receptor ◽  
Inhibitory Effects

Background Sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels in the cardiovascular system may be involved in bupivacaine-induced cardiovascular toxicity. The authors investigated the effects of local anesthetics on the activity of reconstituted KATP channels encoded by inwardly rectifying potassium channel (Kir6.0) and sulfonylurea receptor (SUR) subunits. Methods The authors used an inside-out patch clamp configuration to investigate the effects of bupivacaine, levobupivacaine, and ropivacaine on the activity of reconstituted KATP channels expressed in COS-7 cells and containing wild-type, mutant, or chimeric SURs. Results Bupivacaine inhibited the activities of cardiac KATP channels (IC50 = 52 microm) stereoselectively (levobupivacaine, IC50 = 168 microm; ropivacaine, IC50 = 249 microm). Local anesthetics also inhibited the activities of channels formed by the truncated isoform of Kir6.2 (Kir6.2 delta C36) stereoselectively. Mutations in the cytosolic end of the second transmembrane domain of Kir6.2 markedly decreased both the local anesthetics' affinity and stereoselectivity. The local anesthetics blocked cardiac KATP channels with approximately eightfold higher potency than vascular KATP channels; the potency depended on the SUR subtype. The 42 amino acid residues at the C-terminal tail of SUR2A, but not SUR1 or SUR2B, enhanced the inhibitory effect of bupivacaine on the Kir6.0 subunit. Conclusions Inhibitory effects of local anesthetics on KATP channels in the cardiovascular system are (1) stereoselective: bupivacaine was more potent than levobupivacaine and ropivacaine; and (2) tissue specific: local anesthetics blocked cardiac KATP channels more potently than vascular KATP channels, via the intracellular pore mouth of the Kir6.0 subunit and the 42 amino acids at the C-terminal tail of the SUR2A subunit, respectively.

scholarly journals Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system

2015 ◽  
Vol 78 ◽  
pp. 116-122 ◽  
Author(s):  
Yoshiyuki Ikeda ◽  
Akihiro Shirakabe ◽  
Christopher Brady ◽  
Daniela Zablocki ◽  
Mitsuru Ohishi ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Functional Roles

scholarly journals Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

2019 ◽  
Vol 116 (3) ◽  
pp. 721-735 ◽  
Author(s):  
Francisco J Rios ◽  
Zhi-Guo Zou ◽  
Adam P Harvey ◽  
Katie Y Harvey ◽  
Ryszard Nosalski ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Cardiac Fibroblasts ◽  
Nuclear Antigen ◽  
Culture Systems ◽  
Transient Receptor Potential Melastatin ◽  
Galectin 3 ◽  
Deficient Mice

Abstract Aims Transient Receptor Potential Melastatin 7 (TRPM7) cation channel is a chanzyme (channel + kinase) that influences cellular Mg2+ homeostasis and vascular signalling. However, the pathophysiological significance of TRPM7 in the cardiovascular system is unclear. The aim of this study was to investigate the role of this chanzyme in the cardiovascular system focusing on inflammation and fibrosis. Methods and results TRPM7-deficient mice with deletion of the kinase domain (TRPM7+/Δkinase) were studied and molecular mechanisms investigated in TRPM7+/Δkinase bone marrow-derived macrophages (BMDM) and co-culture systems with cardiac fibroblasts. TRPM7-deficient mice had significant cardiac hypertrophy, fibrosis, and inflammation. Cardiac collagen and fibronectin content, expression of pro-inflammatory mediators (SMAD3, TGFβ) and cytokines [interleukin (IL)-6, IL-10, IL-12, tumour necrosis factor-α] and phosphorylation of the pro-inflammatory signalling molecule Stat1, were increased in TRPM7+/Δkinase mice. These processes were associated with infiltration of inflammatory cells (F4/80+CD206+ cardiac macrophages) and increased galectin-3 expression. Cardiac [Mg2+]i, but not [Ca2+]i, was reduced in TRPM7+/Δkinase mice. Calpain, a downstream TRPM7 target, was upregulated (increased expression and activation) in TRPM7+/Δkinase hearts. Vascular functional and inflammatory responses, assessed in vivo by intra-vital microscopy, demonstrated impaired neutrophil rolling, increased neutrophil: endothelial attachment and transmigration of leucocytes in TRPM7+/Δkinase mice. TRPM7+/Δkinase BMDMs had increased levels of galectin-3, IL-10, and IL-6. In co-culture systems, TRPM7+/Δkinase macrophages increased expression of fibronectin, proliferating cell nuclear antigen, and TGFβ in cardiac fibroblasts from wild-type mice, effects ameliorated by MgCl2 treatment. Conclusions We identify a novel anti-inflammatory and anti-fibrotic role for TRPM7 and suggest that its protective effects are mediated, in part, through Mg2+-sensitive processes.

scholarly journals Cardiovascular adaptations to particle inhalation exposure: molecular mechanisms of the toxicology

2020 ◽  
Vol 319 (2) ◽  
pp. H282-H305
Author(s):  
Amina Kunovac ◽  
Quincy A. Hathaway ◽  
Mark V. Pinti ◽  
Andrew D. Taylor ◽  
John M. Hollander
Keyword(s):  
Particulate Matter ◽  
Cardiovascular System ◽  
Molecular Mechanisms ◽  
Clinical Decision Making ◽  
Inhalation Exposure ◽  
Ambient Air ◽  
Consumer Products ◽  
Comprehensive Overview ◽  
Particle Inhalation ◽  
The Impact

Ambient air, occupational settings, and the use and distribution of consumer products all serve as conduits for toxicant exposure through inhalation. While the pulmonary system remains a primary target following inhalation exposure, cardiovascular implications are exceptionally culpable for increased morbidity and mortality. The epidemiological evidence for cardiovascular dysfunction resulting from acute or chronic inhalation exposure to particulate matter has been well documented, but the mechanisms driving the resulting disturbances remain elusive. In the current review, we aim to summarize the cellular and molecular mechanisms that are directly linked to cardiovascular health following exposure to a variety of inhaled toxicants. The purpose of this review is to provide a comprehensive overview of the biochemical changes in the cardiovascular system following particle inhalation exposure and to highlight potential biomarkers that exist across multiple exposure paradigms. We attempt to integrate these molecular signatures in an effort to provide direction for future investigations. This review also characterizes how molecular responses are modified in at-risk populations, specifically the impact of environmental exposure during critical windows of development. Maternal exposure to particulate matter during gestation can lead to fetal epigenetic reprogramming, resulting in long-term deficits to the cardiovascular system. In both direct and indirect (gestational) exposures, connecting the biochemical mechanisms with functional deficits outlines pathways that can be targeted for future therapeutic intervention. Ultimately, future investigations integrating “omics”-based approaches will better elucidate the mechanisms that are altered by xenobiotic inhalation exposure, identify biomarkers, and guide in clinical decision making.

Cellular and molecular effects of mechanical stretch on vascular cells and cardiac myocytes

2009 ◽  
Vol 116 (5) ◽  
pp. 377-389 ◽  
Author(s):  
Kou-Gi Shyu
Keyword(s):  
Shear Stress ◽  
Cardiovascular Diseases ◽  
Cardiovascular System ◽  
Cardiac Myocytes ◽  
Molecular Mechanisms ◽  
Atherosclerotic Lesion ◽  
Mechanical Stretch ◽  
Vascular Cells ◽  
Molecular Effects ◽  
The Impact

Cells in the cardiovascular system are permanently subjected to mechanical forces due to the pulsatile nature of blood flow and shear stress, created by the beating heart. These haemodynamic forces play an important role in the regulation of vascular development, remodelling, wound healing and atherosclerotic lesion formation. Mechanical stretch can modulate several different cellular functions in VSMCs (vascular smooth muscle cells). These functions include, but are not limited to, cell alignment and differentiation, migration, survival or apoptosis, vascular remodelling, and autocrine and paracrine functions. Laminar shear stress exerts anti-apoptotic, anti-atherosclerotic and antithrombotic effects on ECs (endothelial cells). Mechanical stretch of cardiac myocytes can modulate growth, apoptosis, electric remodelling, alterations in gene expression, and autocrine and paracrine effects. The aim of the present review is primarily to summarize the cellular and molecular effects of mechanical stretch on vascular cells and cardiac myocytes, emphasizing the molecular mechanisms underlying the regulation. Knowledge of the impact of mechanical stretch on the cardiovascular system is vital to the understanding of the pathogenesis of cardiovascular diseases, and is also crucial to provide new insights into the prevention and therapy of cardiovascular diseases.

scholarly journals Research progress of ghrelin on cardiovascular disease

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Ming-Jie Yuan ◽  
Wei Li ◽  
Peng Zhong
Keyword(s):  
Cardiovascular System ◽  
Molecular Mechanisms ◽  
Research Progress ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Vascular Activity ◽  
Cardioprotective Effects ◽  
Pharmacological Potential ◽  
Sympathetic Nerve Activation ◽  
Anti Inflammation

Abstract Ghrelin, a 28-aminoacid peptide, was isolated from the human and rat stomach and identified in 1999 as an endogenous ligand for the growth hormone secretagogue-receptor (GHS-R). In addition to stimulating appetite and regulating energy balance, ghrelin and its receptor GHS-R1a have a direct effect on the cardiovascular system. In recent years, it has been shown that ghrelin exerts cardioprotective effects, including the modulation of sympathetic activity and hypertension, enhancement of the vascular activity and angiogenesis, inhibition of arrhythmias, reduction in heart failure and inhibition of cardiac remodeling after myocardial infarction (MI). The cardiovascular protective effect of ghrelin may be associated with anti-inflammation, anti-apoptosis, inhibited sympathetic nerve activation, regulated autophagy, and endothelial dysfunction. However, the molecular mechanisms underlying the effects of ghrelin on the cardiovascular system have not been fully elucidated, and no specific therapeutic agent has been established. It is important to further explore the pharmacological potential of ghrelin pathway modulation for the treatment of cardiovascular diseases.

scholarly journals Rehabilitation of Patients with Severe Disability after coVID-19 in Rehabilitation Department. Multiple Case Study

2021 ◽  
Vol 20 (3) ◽  
pp. 16-25
Author(s):  
Vladimir E. Vladimirsky ◽  
Evgeniy V. Vladimirsky ◽  
Anna N. Lunina ◽  
Anatoliy D. Fesyun ◽  
Andrey P. Rachin ◽  
...  
Keyword(s):  
Physical Activity ◽  
Cardiovascular System ◽  
Molecular Mechanisms ◽  
Physical Exertion ◽  
Metabolic Demand ◽  
Scientific Publications ◽  
Beneficial Effects ◽  
Physical Exercises ◽  
Multiple Case

The review analyzes the data of scientific publications on the effects of molecular mechanisms initiated by physical exertion on thefunction of the cardiovascular system and the course of cardiac diseases. As practice and a number of evidence-based studies haveshown, the beneficial effects of physical activity on the outcomes of diseases in a number of cardiac nosologies are comparable todrug treatment. Numerous mechanisms mediate the benefits of regular exercise for optimal cardiovascular function. Exercises causewidespread changes in numerous cells, tissues, and organs in response to increased metabolic demand, including adaptation of thecardiovascular system. Physical exercises, which include various types of aerobic exercises of varying intensity and duration, is animportant component of the therapeutic treatment of patients with cardiovascular diseases. Knowledge of the molecular basis ofthe physical activity impact on the cardiovascular system makes it possible to use biochemical markers to assess the effectiveness ofrehabilitation programs.

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