Modification of alterations in cardiac function and sarcoplasmic reticulum by astragaloside IV in myocardial injury in vivo

Background Exosomes are small extracellular vesicles that function as intercellular messengers and effectors. Exosomal cargo contains regulatory small molecules, including mi RNA s, mRNA s, lnc RNA s, and small peptides that can be modulated by different pathological stimuli to the cells. One of the main mechanisms of action of drug therapy may be the altered production and/or content of the exosomes. Methods and Results We studied the effects on exosome production and content by neprilysin inhibitor/angiotensin receptor blockers, sacubitril/valsartan and valsartan alone, using human‐induced pluripotent stem cell‐derived cardiomyocytes under normoxic and hypoxic injury model in vitro , and assessed for physiologic correlation using an ischemic myocardial injury rodent model in vivo. We demonstrated that the treatment with sacubitril/valsartan and valsartan alone resulted in the increased production of exosomes by induced pluripotent stem cell‐derived cardiomyocytes in vitro in both conditions as well as in the rat plasma in vivo. Next‐generation sequencing of these exosomes exhibited downregulation of the expression of rno‐miR‐181a in the sacubitril/valsartan treatment group. In vivo studies employing chronic rodent myocardial injury model demonstrated that miR‐181a antagomir has a beneficial effect on cardiac function. Subsequently, immunohistochemical and molecular studies suggested that the downregulation of miR‐181a resulted in the attenuation of myocardial fibrosis and hypertrophy, restoring the injured rodent heart after myocardial infarction. Conclusions We demonstrate that an additional mechanism of action of the pleiotropic effects of sacubitril/valsartan may be mediated by the modulation of the mi RNA expression level in the exosome payload.

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In vivo effects of nitrosyl hydrogen on cardiac function and sarcoplasmic reticulum calcium pump (SERCA2a) in rats with heart failure after myocardial infarction

Cardiovascular Diagnosis and Therapy ◽

10.21037/cdt-20-201 ◽

2020 ◽

Vol 10 (6) ◽

pp. 1795-1804

Author(s):

Yanqing Guo ◽

Jiyao Xu ◽

Yongzhi Deng ◽

Li Wu ◽

Jingping Wang ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Sarcoplasmic Reticulum ◽

Cardiac Function ◽

Calcium Pump ◽

In Vivo Effects ◽

Sarcoplasmic Reticulum Calcium

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Abstract P134: Synoviolin Is a Stress-Inducible Endoplasmic/Sarcoplasmic Reticulum E3 Ubiquitin Ligase that Preserves Cardiac Function

Circulation Research ◽

10.1161/res.109.suppl_1.ap134 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Shirin Doroudgar ◽

Donna J Thuerauf ◽

Mohsin Khan ◽

Sadia Mohsin ◽

Mirko Völkers ◽

...

Keyword(s):

Sarcoplasmic Reticulum ◽

Cardiac Function ◽

Cardiac Myocytes ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Neonatal Rat ◽

Endoplasmic Reticulum Stress Response ◽

Mouse Heart ◽

Aortic Banding

We recently reported that synoviolin1 (syvn1) is a novel endoplasmic reticulum stress response (ERSR) protein that is up-regulated in the mouse heart by ATF6, a cardioprotective, nodal transcription factor of the ERSR. Syvn1 is a unique E3 ubiquitin ligase that retrotranslocates misfolded proteins from endoplasmic/sarcoplasmic reticulum (ER/SR) to the cytosol and subsequently polyubiquitinates them, targeting them for degradation. We now report that syvn1 expression is induced with tunicamycin, thapsigargin, and dithiothreitol, ER stressors that activate ATF6. Moreover, adenovirus-mediated syvn1 overexpression in neonatal rat ventricular cardiac myocytes (NRVCMs) increases contractility. Consistent with this finding, syvn1 overexpression increases calcium transient amplitude as well as diastolic calcium. We also find that syvn1 overexpression decreases secretion of MANF, a protective, anti-hypertrophic, ER/SR protein which we find is conditionally secreted when ER/SR calcium is depleted. We also report MANF as the first example of a is protein whose secretion from ventricular myocytes is conditionally dependent on ER/SR calcium. Furthermore, syvn1 reduces the growth of NRVCMs treated with the α-adrenergic agonist, phenylephrine. Moreover, while knockdown of syvn1 in NRVCMs using syvn1-targeted siRNA increases cell death, overexpression of syvn1 promotes cell survival. To investigate the roles of syvn1, in vivo , we examined the effects of syvn1 overexpression in cardiac myocytes in a mouse model of trans-aortic banding. Syvn1 overexpression, in vivo, was achieved by intravenous delivery of recombinant AAV serotype 9 (AAV9; cardiac specific serotype) with MLC2v promoter driving syvn1 expression. Baseline cardiac function, as measured by echocardiography six weeks after gene delivery, shows no difference between AAV9-control and AAV9-syvn1 treated mice. Trans-aortic banding decreases cardiac function in mice injected with AAV9-control. In contrast, cardiac function is preserved in mice injected with AAV9-syvn1. The findings in this study suggest that syvn1 is a novel stress-inducible cardiac E3 ligase with unique functions in regulating protein secretion, maintaining cell viability, and preserving cardiac function.

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Astragaloside IV Attenuates the Myocardial Injury Caused by Adriamycin by Inhibiting Autophagy

Frontiers in Pharmacology ◽

10.3389/fphar.2021.669782 ◽

2021 ◽

Vol 12 ◽

Author(s):

Li-Fei Luo ◽

Lu-Yun Qin ◽

Jian-Xin Wang ◽

Peng Guan ◽

Na Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Function ◽

Cell Apoptosis ◽

Myocardial Injury ◽

Heart Function ◽

Myocardial Cell ◽

Akt Pathway ◽

Cardiomyocyte Hypertrophy ◽

Tunel Staining ◽

Astragaloside Iv

Astragaloside IV (ASIV) is the main active component of Astragalus, and can ameliorate cardiomyocyte hypertrophy, apoptosis and fibrosis. In this experiment, we studied how ASIV reduces the cardiotoxicity caused by adriamycin and protects the heart. To this end, rats were randomly divided into the control, ADR, ADR + ASIV and ASIV groups (n = 6). Echocardiography was used to observe cardiac function, HE staining was used to observe myocardial injury, TUNEL staining was used to observe myocardial cell apoptosis, and immunofluorescence and Western blotting was used to observe relevant proteins expression. Experiments have shown that adriamycin can damage heart function in rats, and increase the cell apoptosis index, autophagy level and oxidative stress level. Further results showed that ADR can inhibit the PI3K/Akt pathway. ASIV treatment can significantly improve the cardiac function of rats treated with ADR and regulate autophagy, oxidative stress and apoptosis. Our findings indicate that ASIV may reduce the heart damage caused by adriamycin by activating the PI3K/Akt pathway.

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Author Correction: In vivo transduction of ETV2 improves cardiac function and induces vascular regeneration following myocardial infarction

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0271-x ◽

2019 ◽

Vol 51 (9) ◽

pp. 1-1 ◽

Cited By ~ 1

Author(s):

Sunghun Lee ◽

Dong Hun Lee ◽

Bong-Woo Park ◽

Ri Youn Kim ◽

Anh Duc Hoang ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Vascular Regeneration

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Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22020722 ◽

2021 ◽

Vol 22 (2) ◽

pp. 722

Author(s):

Yukino Ogura ◽

Kazuko Tajiri ◽

Nobuyuki Murakoshi ◽

DongZhu Xu ◽

Saori Yonebayashi ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Neutrophil Elastase ◽

Myocardial Injury ◽

Flow Cytometric Analysis ◽

Akt Signaling ◽

Border Zone ◽

Terminal Deoxynucleotidyl Transferase ◽

Deficient Mice

Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase in NE activity in patients with MI; however, the role of NE in MI remains unclear. Therefore, the present study aimed to investigate the role of NE in the pathogenesis of MI in mice. NE expression peaked on day 1 in the infarcted hearts. In addition, NE deficiency improved survival and cardiac function post-MI, limiting fibrosis in the noninfarcted myocardium. Sivelestat, an NE inhibitor, also improved survival and cardiac function post-MI. Flow cytometric analysis showed that the numbers of heart-infiltrating neutrophils and inflammatory macrophages (CD11b+F4/80+CD206low cells) were significantly lower in NE-deficient mice than in wild-type (WT) mice. At the border zone between intact and necrotic areas, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells was lower in NE-deficient mice than in WT mice. Western blot analyses revealed that the expression levels of insulin receptor substrate 1 and phosphorylation of Akt were significantly upregulated in NE-knockout mouse hearts, indicating that NE deficiency might improve cardiac survival by upregulating insulin/Akt signaling post-MI. Thus, NE may enhance myocardial injury by inducing an excessive inflammatory response and suppressing Akt signaling in cardiomyocytes. Inhibition of NE might serve as a novel therapeutic target in the treatment of MI.

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Effects of Hyperglycemia on Vascular Smooth Muscle Ca2+Signaling

BioMed Research International ◽

10.1155/2017/3691349 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 6

Author(s):

Nahed El-Najjar ◽

Rashmi P. Kulkarni ◽

Nancy Nader ◽

Rawad Hodeify ◽

Khaled Machaca

Keyword(s):

Insulin Resistance ◽

Smooth Muscle ◽

Sarcoplasmic Reticulum ◽

Vascular Smooth Muscle ◽

Complex Disease ◽

Prolonged Exposure ◽

In Vitro System ◽

A7r5 Cells

Diabetes is a complex disease that is characterized with hyperglycemia, dyslipidemia, and insulin resistance. These pathologies are associated with significant cardiovascular implications that affect both the macro- and microvasculature. It is therefore important to understand the effects of various pathologies associated with diabetes on the vasculature. Here we directly test the effects of hyperglycemia on vascular smooth muscle (VSM) Ca2+signaling in an isolated in vitro system using the A7r5 rat aortic cell line as a model. We find that prolonged exposure of A7r5 cells to hyperglycemia (weeks) is associated with changes to Ca2+signaling, including most prominently an inhibition of the passive ER Ca2+leak and the sarcoplasmic reticulum Ca2+-ATPase (SERCA). To translate these findings to the in vivo condition, we used primary VSM cells from normal and diabetic subjects and find that only the inhibition of the ER Ca2+leaks replicates in cells from diabetic donors. These results show that prolonged hyperglycemia in isolation alters the Ca2+signaling machinery in VSM cells. However, these alterations are not readily translatable to the whole organism situation where alterations to the Ca2+signaling machinery are different.

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p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in α-tropomyosin Glu180Gly transgenic mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00237.2013 ◽

2013 ◽

Vol 305 (7) ◽

pp. H1010-H1019 ◽

Cited By ~ 10

Author(s):

Catherine L. Passariello ◽

Marjorie Gayanilo ◽

Michael D. Kritzer ◽

Hrishikesh Thakur ◽

Zoharit Cozacov ◽

...

Keyword(s):

Heart Failure ◽

Transgenic Mice ◽

Cardiac Function ◽

Interstitial Fibrosis ◽

Cardiac Insufficiency ◽

S6 Kinase ◽

Transgenic Expression ◽

P90 Ribosomal S6 Kinase ◽

Ribosomal S6 Kinase

Myocardial interstitial fibrosis is an important contributor to the development of heart failure. Type 3 p90 ribosomal S6 kinase (RSK3) was recently shown to be required for concentric myocyte hypertrophy under in vivo pathological conditions. However, the role of RSK family members in myocardial fibrosis remains uninvestigated. Transgenic expression of α-tropomyosin containing a Glu180Gly mutation (TM180) in mice of a mixed C57BL/6:FVB/N background induces a cardiomyopathy characterized by a small left ventricle, interstitial fibrosis, and diminished systolic and diastolic function. Using this mouse model, we now show that RSK3 is required for the induction of interstitial fibrosis in vivo. TM180 transgenic mice were crossed to RSK3 constitutive knockout ( RSK3−/−) mice. Although RSK3 knockout did not affect myocyte growth, the decreased cardiac function and mild pulmonary edema associated with the TM180 transgene were attenuated by RSK3 knockout. The improved cardiac function was consistent with reduced interstitial fibrosis in the TM180; RSK3−/− mice as shown by histology and gene expression analysis, including the decreased expression of collagens. The specific inhibition of RSK3 should be considered as a potential novel therapeutic strategy for improving cardiac function and the prevention of sudden cardiac death in diseases in which interstitial fibrosis contributes to the development of heart failure.

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