scholarly journals Role of PI3-Kinase in Angiotensin II-Induced Cardiac Hypertrophy: Class I Versus Class III

2021 ◽  
Vol 12 ◽  
Author(s):  
Tiecheng Zhong ◽  
Zonggui Wang ◽  
Sayeman Islam Niloy ◽  
Yue Shen ◽  
Stephen T. O’Rourke ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Class I ◽  
Cardiomyocyte Hypertrophy ◽  
Ros Production ◽  
Ang Ii ◽  
Class Iii ◽  
Mitochondrial Ros ◽  
Autophagy Activity

Cardiac hypertrophy is an adaptive response to cardiac overload initially but turns into a decompensated condition chronically, leading to heart failure and sudden cardiac death. The molecular mechanisms involved in cardiac hypertrophy and the signaling pathways that contribute to the switch from compensation to decompensation are not fully clear. The aim of the current study was to examine the role of PI3-kinases Class I (PI3KC1) and Class III (PI3KC3) in angiotensin (Ang) II-induced cardiac hypertrophy. The results demonstrate that treatment of cardiomyocytes with Ang II caused dose-dependent increases in autophagy, with an increasing phase followed by a decreasing phase. Ang II-induced autophagic increases were potentiated by inhibition of PI3KC1 with LY294002, but were impaired by inhibition of PI3KC3 with 3-methyladenine (3-MA). In addition, blockade of PI3KC1 significantly attenuated Ang II-induced ROS production and cardiomyocyte hypertrophy. In contrast, blockade of PI3KC3 potentiated Ang II-induced ROS production and cardiac hypertrophy. Moreover, blockade of PI3KC1 by overexpression of dominant negative p85 subunit of PI3KC1 significantly attenuated Ang II-induced cardiac hypertrophy in normotensive rats. Taken together, these results demonstrate that both PI3KC1 and PI3KC3 are involved in Ang II-induced cardiac hypertrophy by different mechanisms. Activation of PI3KC1 impairs autophagy activity, leading to accumulation of mitochondrial ROS, and, hence, cardiac hypertrophy. In contrast, activation of PI3KC3 improves autophagy activity, thereby reducing mitochondrial ROS and leads to a protective effect on Ang II-induced cardiac hypertrophy.

scholarly journals Caspase-1 regulates Ang II-induced cardiomyocyte hypertrophy via up-regulation of IL-1β

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Yunlong Bai ◽  
Xi Sun ◽  
Qun Chu ◽  
Anqi Li ◽  
Ying Qin ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Compensatory Response ◽  
Caspase 1

Cardiac hypertrophy is a compensatory response to stress or stimuli, which results in arrhythmia and heart failure. Although multiple molecular mechanisms have been identified, cardiac hypertrophy is still difficult to treat. Pyroptosis is a caspase-1-dependent pro-inflammatory programmed cell death. Caspase-1 is involved in various types of diseases, including hepatic injury, cancers, and diabetes-related complications. However, the exact role of caspase-1 in cardiac hypertrophy is yet to be discovered. The present study aimed to explore the possible role of caspase-1 in pathogenesis of cardiac hypertrophy. We established cardiac hypertrophy models both in vivo and in vitro to detect the expression of caspase-1 and interleukin-1β (IL-1β). The results showed that caspase-1 and IL-1β expression levels were significantly up-regulated during cardiac hypertrophy. Subsequently, caspase-1 inhibitor was co-administered with angiotensin II (Ang II) in cardiomyocytes to observe whether it could attenuate cardiac hypertrophy. Results showed that caspase-1 attenuated the pro-hypertrophic effect of Ang II, which was related to the down-regulation of caspase-1 and IL-1β. In conclusion, our results provide a novel evidence that caspase-1 mediated pyroptosis is involved in cardiac hypertrophy, and the inhibition of caspase-1 will offer a therapeutic potential against cardiac hypertrophy.

scholarly journals Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes

2021 ◽  
Vol 8 ◽  
Author(s):  
Ran Xu ◽  
Le Kang ◽  
Siang Wei ◽  
Chunjie Yang ◽  
Yuanfeng Fu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Marker Genes ◽  
Autophagic Flux ◽  
Ang Ii ◽  
Neonatal Cardiomyocytes ◽  
Primary Mouse

Pathological cardiac hypertrophy, the adaptive response of the myocardium to various pathological stimuli, is one of the primary predictors and predisposing factors of heart failure. However, its molecular mechanisms underlying pathogenesis remain poorly understood. Here, we studied the function of Samm50 in mitophagy during Ang II-induced cardiomyocyte hypertrophy via lentiviruses mediated knockdown and overexpression of Samm50 protein. We first found that Samm50 is a key positive regulator of cardiac hypertrophy, for western blot and real-time quantitative PCR detection revealed Samm50 was downregulated both in pressure-overload-induced hypertrophic hearts and Ang II-induced cardiomyocyte hypertrophy. Then, Samm50 overexpression exhibits enhanced induction of cardiac hypertrophy marker genes and cell enlargement in primary mouse cardiomyocytes by qPCR and immunofluorescence analysis, respectively. Meanwhile, Samm50 remarkably reduced Ang II-induced autophagy as indicated by decreased mitophagy protein levels and autophagic flux, whereas the opposite phenotype was observed in Samm50 knockdown cardiomyocytes. However, the protective role of Samm50 deficiency against cardiac hypertrophy was abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown. Moreover, we further demonstrated that Samm50 interacted with Pink1 and stimulated the accumulation of Parkin on mitochondria to initiate mitophagy by co-immunoprecipitation analysis and immunofluorescence. Thus, these results suggest that Samm50 regulates Pink1-Parkin-mediated mitophagy to promote cardiac hypertrophy, and targeting mitophagy may provide new insights into the treatment of cardiac hypertrophy.

scholarly journals Role of PI3‐kinase in Angiotensin II‐induced Cardiac Hypertrophy: Shift from Class III to Class I

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Tiecheng Zhong ◽  
Lirong Guo ◽  
Stephen T. O'Rourke ◽  
Chengwen Sun
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Pi3 Kinase ◽  
Class I ◽  
Class Iii

scholarly journals Novel Therapeutic Effects of Pterosin B on Ang II-Induced Cardiomyocyte Hypertrophy

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5279
Author(s):  
Chang Youn Lee ◽  
Han Ki Park ◽  
Bok-Sim Lee ◽  
Seongtae Jeong ◽  
Sung-Ae Hyun ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Therapeutic Effects ◽  
Ang Ii ◽  
Pathological Cardiac Hypertrophy ◽  
Glycation End Products ◽  
Abnormal Increase

Pathological cardiac hypertrophy is characterized by an abnormal increase in cardiac muscle mass in the left ventricle, resulting in cardiac dysfunction. Although various therapeutic approaches are being continuously developed for heart failure, several studies have suggested natural compounds as novel potential strategies. Considering relevant compounds, we investigated a new role for Pterosin B for which the potential life-affecting biological and therapeutic effects on cardiomyocyte hypertrophy are not fully known. Thus, we investigated whether Pterosin B can regulate cardiomyocyte hypertrophy induced by angiotensin II (Ang II) using H9c2 cells. The antihypertrophic effect of Pterosin B was evaluated, and the results showed that it reduced hypertrophy-related gene expression, cell size, and protein synthesis. In addition, upon Ang II stimulation, Pterosin B attenuated the activation and expression of major receptors, Ang II type 1 receptor and a receptor for advanced glycation end products, by inhibiting the phosphorylation of PKC-ERK-NF-κB pathway signaling molecules. In addition, Pterosin B showed the ability to reduce excessive intracellular reactive oxygen species, critical mediators for cardiac hypertrophy upon Ang II exposure, by regulating the expression levels of NAD(P)H oxidase 2/4. Our results demonstrate the protective role of Pterosin B in cardiomyocyte hypertrophy, suggesting it is a potential therapeutic candidate.

Abstract 309: Small Heterodimer Partner Blocks Cardiac Hypertrophy By Interfering With GATA6 Signaling

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Yoon Seok Nam ◽  
Duk-Hwa Kwon ◽  
Gwang Hyeon Eom ◽  
Hyun Kook
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Diseases ◽  
Cardiomyocyte Hypertrophy ◽  
Physical Interaction ◽  
Orphan Nuclear Receptor ◽  
Promoter Regions ◽  
Adult Heart ◽  
Hypertrophic Response ◽  
Small Heterodimer Partner

Rationale: Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA binding domain. By interacting with other transcription factors, SHP regulates diverse biological events including glucose metabolism in liver. The role of SHP in adult heart diseases has not yet been demonstrated. Objective: We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy. Methods and Results: The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of cardiomyocyte hypertrophy. SHP reduced the protein amount of Gata6. By direct physical interaction with Gata6, SHP interfered with the binding of Gata6 to GATA binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an anti-diabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin-induced anti-hypertrophic effect was attenuated either by SHP siRNA in cardiomyocytes or in SHP null mice. Conclusions: These results establish SHP as a novel anti-hypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced anti-hypertrophic response.

scholarly journals The Role of Sirtuins in Kidney Diseases

2020 ◽  
Vol 21 (18) ◽  
pp. 6686
Author(s):  
Yu Ah Hong ◽  
Ji Eun Kim ◽  
Minjee Jo ◽  
Gang-Jee Ko
Keyword(s):  
Histone Deacetylases ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Expression Profiles ◽  
Kidney Injury ◽  
Class Iii ◽  
Cellular Functions ◽  
Wide Range

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

scholarly journals Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

2015 ◽  
Vol 36 (4) ◽  
pp. 1597-1612 ◽  
Author(s):  
Lei Liu ◽  
Chao Wang ◽  
Dianjun Sun ◽  
Shuangquan Jiang ◽  
Hong Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Intracellular Calcium Concentration ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Sham Operation ◽  
Ang Ii

Background/Aims: Intracellular calcium concentration ([Ca2+]i) homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR) and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex231, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Methods: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E) or Masson's trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca2+]i) was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. Results: The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex231. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex231 suppressed CaSR expression and downregulated autophagy by inhibiting the Ca2+/calmodulin-dependent-protein kinase-kinase-β (CaMKKβ)- AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway to ameliorate cardiomyocyte hypertrophy. Conclusions: Calhex231 ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex231 can become a new therapeutic agent for the treatment of cardiac hypertrophy.

Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy

2006 ◽  
Vol 26 (3) ◽  
pp. 180-191 ◽  
Author(s):  
Shawn D. Hingtgen ◽  
Xin Tian ◽  
Jusan Yang ◽  
Shannon M. Dunlay ◽  
Andrew S. Peek ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Dominant Negative ◽  
Time Dependent ◽  
Neonatal Rat ◽  
Signaling Cascade ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Akt Activation

Angiotensin II (ANG II) has profound effects on the development and progression of pathological cardiac hypertrophy; however, the intracellular signaling mechanisms are not fully understood. In this study, we used genetic tools to test the hypothesis that increased formation of superoxide (O2−·) radicals from a Rac1-regulated Nox2-containing NADPH oxidase is a key upstream mediator of ANG II-induced activation of serine-threonine kinase Akt, and that this signaling cascade plays a crucial role in ANG II-dependent cardiomyocyte hypertrophy. ANG II caused a significant time-dependent increase in Rac1 activation and O2−· production in primary neonatal rat cardiomyocytes, and these responses were abolished by adenoviral (Ad)-mediated expression of a dominant-negative Rac1 (AdN17Rac1) or cytoplasmic Cu/ZnSOD (AdCu/ZnSOD). Moreover, both AdN17Rac1 and AdCu/ZnSOD significantly attenuated ANG II-stimulated increases in cardiomyocyte size. Quantitative real-time PCR analysis demonstrated that Nox2 is the homolog expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by >95% and abolished both ANG II-induced O2−· generation and cardiomyocyte hypertrophy. Finally, ANG II caused a time-dependent increase in Akt activity via activation of AT1 receptors, and this response was abolished by Ad-mediated expression of cytosolic human O2−· dismutase (AdCu/ZnSOD). Furthermore, pretreatment of cardiomyocytes with dominant-negative Akt (AdDNAkt) abolished ANG II-induced cellular hypertrophy. These findings suggest that O2−· generated by a Nox2-containing NADPH oxidase is a central mediator of ANG II-induced Akt activation and cardiomyocyte hypertrophy, and that dysregulation of this signaling cascade may play an important role in cardiac hypertrophy.

Molecular mechanisms of GABAB receptor activation: new insights from the mechanism of action of CGP7930, a positive allosteric modulator

2004 ◽  
Vol 32 (5) ◽  
pp. 871-872 ◽  
Author(s):  
V. Binet ◽  
C. Goudet ◽  
C. Brajon ◽  
L. Le Corre ◽  
F. Acher ◽  
...  
Keyword(s):  
G Protein ◽  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Gabab Receptor ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Class Iii ◽  
G Protein Coupled ◽  
New Strategies

The GABAB (γ-aminobutyric acid-B) receptor is composed of two subunits, GABAB1 and GABAB2. Both subunits share structural homology with other class-III G-protein-coupled receptors. They contain two main domains, a heptahelical domain typical of all G-protein-coupled receptors and a large ECD (extracellular domain). It has not been demonstrated whether the association of these two subunits is always required for function. However, GABAB2 plays a major role in coupling with G-proteins, and GABAB1 has been shown to bind GABA. To date, only ligands interacting with GABAB1-ECD have been identified. In the present study, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABAB receptor. We have shown that it can weakly activate the wild-type GABAB receptor, but also the GABAB2 expressed alone, thus being the first described agonist of GABAB2. CGP7930 retains its weak agonist activity on a GABAB2 subunit deleted of its ECD. Thus the heptahelical domain of GABAB2 behaves similar to a rhodopsin-like receptor. These results open new strategies for studying the mechanism of activation of GABAB receptor and examine any possible role of GABAB2.

scholarly journals Role of CyPA in cardiac hypertrophy and remodeling

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Mengfei Cao ◽  
Wei Yuan ◽  
Meiling Peng ◽  
Ziqi Mao ◽  
Qianru Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy ◽  
Complex Process

Abstract Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress, involving increased interstitial fibrosis, cell death and cardiac dysfunction. Studies have shown that oxidative stress is an important mechanism for this maladaptation. Cyclophilin A (CyPA) is a member of the cyclophilin (CyPs) family. Many cells secrete CyPA to the outside of the cells in response to oxidative stress. CyPA from blood vessels and the heart itself participate in a variety of signaling pathways to regulate the production of reactive oxygen species (ROS) and mediate inflammation, promote cardiomyocyte hypertrophy and proliferation of cardiac fibroblasts, stimulate endothelial injury and vascular smooth muscle hyperplasia, and promote the dissolution of extracellular matrix (ECM) by activating matrix metalloproteinases (MMPs). The events triggered by CyPA cause a decline of diastolic and systolic function and finally lead to the occurrence of heart failure. This article aims to introduce the role and mechanism of CyPA in cardiac hypertrophy and remodeling, and highlights its potential role as a disease biomarker and therapeutic target.

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