Abstract 266: Novel Sites of Angiotension II Type 1 Receptor are Identified for Direct Activation by Mechanical Stretch Independent of Angiotension II

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Hui Gong ◽  
Guoliang Jiang ◽  
Chunjie Yang ◽  
Shijun Wang ◽  
Zhidan Chen ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Pressure Overload ◽  
Mechanical Stretch ◽  
Site Directed Mutagenesis ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Angiotension Ii ◽  
High Level

The angiotensin II type 1 receptor (AT1R) has a crucial role in cardiac hypertrophy induced by pressure overload. In the previous study, we found a novel mechanism for mechanical stress-induced AT1R activation without the involvement of Ang II. However, few reports focus on how AT1R senses mechanical stress and translates it into biochemical signals inside the cells to induce cardiomyocyte hypertrophy. Here, we constructed different site-directed mutagenesis of AT1R and transfected them to COS7 cells and ATG–/– (Angiotensinogen knockout) cardiomyocytes, respectively, to observe the activation of downstream signaling to identify functional site of AT1R. The results showed AT1R-WT, AT1R-K199Q, AT1R-L212F,AT1R-Q257A and AT1R-C289A plasmids or adenovirus were overexpressed at high level in plasma membrane of COS7 or cardiomyocytes respectively. There was no obvious difference in subcellular expression of wt-AT1R and all the mut-AT1Rs. The further study revealed that Ang II-induced-phosphorylation of ERK, Jak2 and the redistribution of Gαq11 were dramatically decreased in COS7 cells expressing AT1R-K199Q or AT1R-Q257A, while these effects induced by mechanical stretch were greatly suppressed in COS7 cells expressing AT1R-L212F,AT1R-Q257A or AT1R-C289A compared to these in COS7 cells expressing AT1R-WT. We then transfected the adenovirus of wt-AT1R or different mut-AT1Rs to ATG–/– cardiomyocytes to exclude the influence of endogenous Ang II. The results were consistent with these results in COS7 cells. Moreover, ATG–/– cardiomyocytes overexpressing AT1R-K199Q or AT1R-Q257A parlty abolished hypertrophic response induce by Ang II, while the cardiomyocytes overexpressing AT1R-L212F,AT1R-Q257A or AT1R-C289A greatly inhibited the hypertrophic response induced by mechanical stretch. The present study indicated that Leu212, Gln257 and Cys289 are critical sites for AT1R activation by mechanical stretch without Ang II but Lys199 and Gln257 play important role in AT1R activation with Ang II.

scholarly journals The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation

2019 ◽  
Vol 5 (5) ◽  
pp. eaau0495 ◽  
Author(s):  
Xin Xie ◽  
Hai-Lian Bi ◽  
Song Lai ◽  
Yun-Long Zhang ◽  
Nan Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Inflammatory Diseases ◽  
Pressure Overload ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Adequate Treatment ◽  
Hypertrophic Response ◽  
Pathological Cardiac Hypertrophy ◽  
Mediated Reduction ◽  
Expression And Activity

Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. The immunoproteasome is an inducible form of the proteasome that is intimately involved in inflammatory diseases. Here, we found that the expression and activity of immunoproteasome catalytic subunit β5i were significantly up-regulated in angiotensin II (Ang II)–treated cardiomyocytes and in the hypertrophic hearts. Knockout of β5i in cardiomyocytes and mice markedly attenuated the hypertrophic response, and this effect was aggravated by β5i overexpression in cardiomyocytes and transgenic mice. Mechanistically, β5i interacted with and promoted ATG5 degradation thereby leading to inhibition of autophagy and cardiac hypertrophy. Further, knockdown of ATG5 or inhibition of autophagy reversed the β5i knockout-mediated reduction of cardiomyocyte hypertrophy induced by Ang II or pressure overload. Together, this study identifies a novel role for β5i in the regulation of cardiac hypertrophy. The inhibition of β5i activity may provide a new therapeutic approach for hypertrophic diseases.

Abstract 257: PP2Cm Regulation Links Branched Chain Amino Acid with Hypertrophy Response

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Meiyi Zhou ◽  
Zhihua Wang ◽  
Darwin Jeyaraj ◽  
Bangfen Pan ◽  
Ying Huang ◽  
...  
Keyword(s):  
Mrna Level ◽  
Mitochondrial Protein ◽  
Pressure Overload ◽  
Hypertrophic Response ◽  
Branched Chain Amino Acid ◽  
Rate Limiting Step ◽  
Branched Chain ◽  
High Level ◽  
Mtor Activity

[Introduction] Branched Chain Amino Acids (BCAAs), including leucine, isoleucine, and valine, modulate mTOR activity that controls protein synthesis and cell growth. PP2Cm is a mitochondrial protein phosphatase that regulates the rate limiting step of BCAA degradation. Loss of PP2Cm leads to BCAA accumulation. [Hypothesis] PP2Cm downregulation by hypertrophic signal impairs BCAA catabolism and thus hypertrophy response in heart. [Methods and Results] High level of PP2Cm is expressed in heart through all development stages. PP2Cm expression was reduced in hypertrophic heart induced by pressure overload, corresponding with increase of BCAA level and mTOR activity. KLF15 and microRNA22 are both key regulators of hypertrophy. It has been shown that hypertrophy signal s upregulated microRNA22 while decreasing KLF15 expression. We found that KLF15 increased PP2Cm promoter activity and miRNA22 regulated PP2Cm mRNA level and protein expression via 3’UTR . Together, our data indicated that hypertrophy inducers down-regulates KLF15 while increasing miRNA22, resulting in decreased PP2Cm level and thus repressed BCAA catabolism, which in turn can impact on mTOR mediated signaling and activity. [Conclusions] Pathological stress may affect the expression of PP2Cm and influence the outcome of hypertrophic response, suggesting an important role of BCAA nutrient and PP2Cm expression in heart.

Abstract 16434: IL-6 Signaling is Crucial for Cardiomyocyte Hypertrophy and Left Ventricular Dysfunction Induced by Pressure Overload

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Lin Zhao ◽  
Guangming Cheng ◽  
Yanjuan Yang ◽  
Anweshan Samanta ◽  
Rizwan R Afzal ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Function ◽  
Ang Ii ◽  
Adult Cardiomyocytes

Introduction: Interleukin-6 (IL-6), a proinflammatory cytokine, has been implicated in ischemic cardiac pathologies. Very little is currently known regarding the role of IL-6 signaling in pathological cardiomyocyte hypertrophy and LV dysfunction. Hypothesis: We hypothesized that IL-6 signaling plays a central role in cardiomyocyte hypertrophy and exerts a deleterious impact on LV remodeling induced by pressure overload. Methods: In vitro, adult cardiomyocytes from C57BL/6 (WT, control) and IL-6 knockout (KO) mice were stimulated by IL-6 and pro-hypertrophic agent angiotensin II (Ang II). The expression of hypertrophy markers and related signaling molecules were examined by real-time quantitative RT-PCR. In vivo, weight-matched male WT and IL-6 KO mice underwent transverse aortic constriction (TAC) or a sham procedure. Serial echocardiograms and a terminal hemodynamic study were performed. Results: After exposure to IL-6 and hypertrophic agonists, the expression of hypertrophy related genes, BNP, GATA-4, αSK actin, and β-MHC increased significantly in WT cardiomyocytes (Fig). These effects were significantly attenuated in IL-6 knockout cardiomyocytes (Fig), indicating an essential role of IL-6 in cardiomyocyte hypertrophy. In vivo, the worsening in LV contraction as well as relaxation after TAC was significantly attenuated in IL-6 KO mice, indicating superior preservation of LV function in the setting of pressure overload in the absence of IL-6 signaling. Conclusions: The protection against Ang II-induced hypertrophy observed in IL-6 KO adult cardiomyocytes in vitro, and in hearts of IL-6 KO mice after TAC in vivo illustrates a crucial role played by IL-6 in pathogenesis of pressure overload-induced LV hypertrophy. Modulation of IL-6 signaling may have preventive therapeutic potential for countless hypertensive patients at risk for LV hypertrophy and failure.

Angiotensin II and mechanical stretch induce production of tumor necrosis factor in cardiac fibroblasts

1999 ◽  
Vol 276 (6) ◽  
pp. H1968-H1976 ◽  
Author(s):  
Tomoyuki Yokoyama ◽  
Kenichi Sekiguchi ◽  
Toru Tanaka ◽  
Koichi Tomaru ◽  
Masashi Arai ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Mechanical Stress ◽  
Cardiac Myocytes ◽  
Tumor Necrosis ◽  
Cardiac Fibroblasts ◽  
Mechanical Stretch ◽  
Intracellular Camp ◽  
Ang Ii ◽  
Tnf Α ◽  
Necrosis Factor

To determine whether ANG II as well as mechanical stress affect the production of tumor necrosis factor (TNF) in the heart, neonatal rat cardiac myocytes and fibroblasts were cultured separately and treated for 6 h with ANG II, lipopolysaccharide (LPS), or cyclic mechanical stretch. LPS induced the production of TNF in cardiac myocytes and fibroblasts. However, TNF synthesis in fibroblasts was 20- to 40-fold higher than in myocytes. ANG II (≥10−8 M) and mechanical stretch stimulated the production of TNF in cardiac fibroblasts but not in myocytes. Furthermore, both ANG II and LPS increased the expression of TNF-α mRNA in cardiac fibroblasts. Isoproterenol inhibited both LPS- and ANG II-induced production of TNF in cardiac fibroblasts with increasing intracellular cAMP level. Moreover, both isoproterenol and dibutyryl cAMP inhibited LPS-induced TNF-α mRNA expression. Thus activation of the renin-angiotensin system, as well as mechanical stress, can stimulate production of TNF in cardiac fibroblasts. Furthermore, β-adrenergic receptors may be responsible for the regulation of TNF synthesis at the transcriptional level by elevating intracellular cAMP.

scholarly journals The Cardiovascular benefits of Empagliflozin, a Sodium Glucose Cotransporter Inhibitor: Is NHE1 a viable target?

2020 ◽  
Author(s):  
Al-Anood Al-Shamasi ◽  
Meram Elsayed ◽  
Nabeel Abdulrahman ◽  
Jensa Joseph ◽  
Fatima Mraiche
Keyword(s):  
Protein Expression ◽  
Sglt2 Inhibitor ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Vascular Events ◽  
Hypertrophic Response ◽  
Trial Treatment ◽  
Nhe1 Activity ◽  
H9c2 Cardiomyoblasts

Empagliflozin (EMPA), an SGLT2 inhibitor (with a low affinity for SGLT1) has attracted much attention due to a recent clinical trial, the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME). In this trial, treatment with EMPA over 2.6 years decreased cardiovascular vascular events (14% reduction). Whether EMPA induces cardioprotection, independent of diabetes remains unclear. A previous report has demonstrated that EMPA inhibited NHE1 activity, which led to a reduction in intracellular sodium and calcium. In our study, we examine the cellular interplay between NHE1 and SGLT1/SGLT2 in a non-diabetic in vitro model. We characterized H9c2 cardiomyoblasts stimulated with Angiotensin II (ANG II) 100nM in the presence and absence of EMPA (500nM) and measured cardiomyocyte hypertrophy and the expression of NHE1 and SGLT1/2. Stimulation of H9c2 cardiomyoblasts with ANG II (100nM) resulted in cardiomyocyte hypertrophy, an effect that was regressed in the presence of EMPA (500nM). No changes in SGLT2 and NHE1 protein expression were detected in H9c2 cardiomyoblasts. However, stimulation with ANG II in the presence of EMPA reduced the expression of SGLT1. We demonstrate that the inhibition of SGLT using EMPA following stimulation with ANG II, a hypertrophic stimulator of cardiomyocyte hypertrophy and NHE1, regressed the hypertrophic response of H9c2 cardiomyoblasts and SGLT1 protein expression. The inhibition of SGLT1 protein expression may be contributing to the anti-hypertrophic effect of EMPA. Whether EMPA reduces NHE1 activity remains to be elucidated.

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 β-Arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury

2012 ◽  
Vol 303 (8) ◽  
pp. H1001-H1010 ◽  
Author(s):  
Ki-Seok Kim ◽  
Dennis Abraham ◽  
Barbara Williams ◽  
Jonathan D. Violin ◽  
Lan Mao ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Contractility ◽  
Cardiac Injury ◽  
Mechanical Stretch ◽  
Ang Ii ◽  
Biased Signaling ◽  
Pharmacological Blockade

Pharmacological blockade of the ANG II type 1 receptor (AT1R) is a common therapy for treatment of congestive heart failure and hypertension. Increasing evidence suggests that selective engagement of β-arrestin-mediated AT1R signaling, referred to as biased signaling, promotes cardioprotective signaling. Here, we tested the hypothesis that a β-arrestin-biased AT1R ligand TRV120023 would confer cardioprotection in response to acute cardiac injury compared with the traditional AT1R blocker (ARB), losartan. TRV120023 promotes cardiac contractility, assessed by pressure-volume loop analyses, while blocking the effects of endogenous ANG II. Compared with losartan, TRV120023 significantly activates MAPK and Akt signaling pathways. These hemodynamic and biochemical effects were lost in β-arrestin-2 knockout (KO) mice. In response to cardiac injury induced by ischemia reperfusion injury or mechanical stretch, pretreatment with TRV120023 significantly diminishes cell death compared with losartan, which did not appear to be cardioprotective. This cytoprotective effect was lost in β-arrestin-2 KO mice. The β-arrestin-biased AT1R ligand, TRV120023, has cardioprotective and functional properties in vivo, which are distinct from losartan. Our data suggest that this novel class of drugs may provide an advantage over conventional ARBs by supporting cardiac function and reducing cellular injury during acute cardiac injury.

Activation of angiotensinogen gene in cardiac myocytes by angiotensin II and mechanical stretch

1998 ◽  
Vol 275 (1) ◽  
pp. R1-R9 ◽  
Author(s):  
Kouichi Tamura ◽  
Satoshi Umemura ◽  
Nobuo Nyui ◽  
Kiyoshi Hibi ◽  
Tomoaki Ishigami ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Promoter Activity ◽  
Actinomycin D ◽  
Mrna Level ◽  
Mechanical Stretch ◽  
Ang Ii ◽  
Angiotensinogen Gene

Circulating and cardiac renin-angiotensin systems (RAS) play important roles in the development of cardiac hypertrophy. Mechanical stretch of cardiac myocytes induces secretion of ANG II and evokes hypertrophic responses. Angiotensinogen is a unique substrate of the RAS. This study was performed to examine the regulation of the angiotensinogen gene in cardiac myocytes in response to ANG II and stretch. ANG II and stretch significantly increased the levels of angiotensinogen mRNA in cardiac myocytes. Actinomycin D completely inhibited ANG II- and stretch-mediated increases in angiotensinogen mRNA. Although CV-11974 abolished ANG II-mediated increases in mRNA level and promoter activity of the angiotensinogen gene, the inhibition of stretch-mediated activation by CV-11974 was significant but not complete. These results indicate that ANG II activates transcription of the angiotensinogen gene exclusively via ANG II type 1-receptor pathway and that stretch activates such transcription mainly via the same pathway in cardiac myocytes. Furthermore, factors other than ANG II may also be involved in stretch-mediated activation of the angiotensinogen gene in cardiac myocytes.

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.

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