Pathological cardiac hypertrophy: the synergy of adenylyl cyclases inhibition in cardiac and immune cells during chronic catecholamine stress

Adzika, Gabriel Komla; Machuki, Jeremiah Ong’achwa; Shang, Wenkang; Hou, Hongjian; Ma, Tran; Wu, Lijuan; Geng, Juan; Hu, Xide; Ma, Xianluo; Sun, Hong

doi:10.1007/s00109-019-01790-0

Cited by 26 publications

(38 citation statements)

References 129 publications

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“…In response to pressure overload, a common stimulus of cardiac hypertrophy, circulating levels of angiotensin II (Ang II), epinephrine, and norepinephrine are elevated. The hormones then bind to their membrane-bound receptors, characterized by the seven-transmembrane topology and coupling to G proteins, to trigger signaling cascades (Adzika et al, 2019). On the other hand, there are counteracting signaling pathways that antagonize cardiac hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

An MRTF-A–Sp1–PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy

Wang

Xin

et al. 2020

Front. Cell Dev. Biol.

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Cardiac hypertrophy is a critical intermediate step in the pathogenesis of heart failure. A myriad of signaling networks converge on cardiomyocytes to elicit hypertrophic growth in response to various injurious stimuli. In the present study, we investigated the cardiomyocyte-specific role of myocardin-related transcription factor A (MRTF-A) in angiotensin-II (Ang-II)-induced cardiac hypertrophy and the underlying mechanism. We report that conditional MRTF-A deletion in cardiomyocytes attenuated Ang-II-induced cardiac hypertrophy in mice. Similarly, MRTF-A knockdown or inhibition suppressed Ang-II-induced prohypertrophic response in cultured cardiomyocytes. Of note, Ang II treatment upregulated expression of phosphodiesterase 5 (PDE5), a known mediator of cardiac hypertrophy and heart failure, in cardiomyocytes, which was blocked by MRTF-A depletion or inhibition. Mechanistically, MRTF-A activated expression of specificity protein 1 (Sp1), which in turn bound to the PDE5 promoter and upregulated PDE5 transcription to promote hypertrophy of cardiomyocytes in response to Ang II stimulation. Therefore, our data unveil a novel MRTF-A-Sp1-PDE5 axis that mediates Ang-II-induced hypertrophic response in cardiomyocytes. Targeting this newly identified MRTF-A-Sp1-PDE5 axis may yield novel interventional solutions against heart failure.

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Section: Introductionmentioning

confidence: 99%

An MRTF-A–Sp1–PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy

Wang

Xin

et al. 2020

Front. Cell Dev. Biol.

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“…The elevated level of circulating catecholamines during chronic stress is a hallmark for the initiation and progression of adverse cardiac remodeling (Paur H et al, 2012;Adzika GK et al, 2019). Pathological cardiac hypertrophy (PCH) is the irreversible resultant cardiomyopathy if there are no timely preventive measures to subdue the excessively firing of neurohormonal stimuli during chronic stress.…”

Section: Introductionmentioning

confidence: 99%

“…The pleiotropic nature of β 2 AR enables it to traffick stimuli via G ας or G αι in cardiomyocytes, and immune cells. Also, a mounting of evidence indicates that β 2 AR mediates maladaptive stimuli signaling during cardiovascular diseases (CVDs) (Paur H et al, 2012;Adzika GK et al, 2019;Laukova M et al, 2018). These suggests exploring the post-β 2 AR proteins and kinases may have therapeutic potentials of attenuating the occurrence of PCH.…”

Section: Introductionmentioning

confidence: 99%

“…These suggests exploring the post-β 2 AR proteins and kinases may have therapeutic potentials of attenuating the occurrence of PCH. Furthermore, a negative correlation exists between ACs and GRKs in healthy and failing cardiac and immune systems (Adzika GK et al, 2019). Therefore, this study focuses on ACs and G protein-coupled receptor kinases (GRKs) to exploit their possible therapeutic potentials.…”

Section: Introductionmentioning

confidence: 99%

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Combination of Amlexanox and Forskolin Attenuates Pathological Cardiac Hypertrophy by Subduing Maladaptive Inflammatory Response

Adzika

Hou

Adekunle

et al. 2020

Preprint

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Background and Purpose: The immune system is implicated in the pathogenesis of pathological cardiac hypertrophy (PCH). However, there is currently no therapeutic intervention to prevent PCH. Here, we aimed at preventing pathological cardiac hypertrophy (PCH) during chronic catecholamine stress via modulating adaptive inflammatory by targeting adenylyl cyclases (ACs) and G protein-coupled receptor kinase 5 (GRK5) in cardiomyocytes and immune cells. Experimental Approach: PCH was induced in mice by chronic isoproterenol injections. In vitro, peritoneal macrophages were challenged with lipopolysaccharide under stress. Further experiments employed the therapeutic interventions Amlexanox and Forskolin to inhibit GRK5 and activate ACs-cAMP, respectively. Cardiac functions were assessed with echocardiography. Inflammatory markers were assessed with ELISA and RT-qPCR (in vivo and in vitro). GRK5 localizations in macrophages were assessed by immunofluorescence, and alterations in protein expression were analyzed with immunoblotting. Histological assessments were done with Masson, H&E and IHC staining. Key Results: PCH mice had deteriorating cardiac functions and morphological remodeling, accompanied by massive immune cell infiltrations. Similarities were observed proinflammatory markers upregulation, as were IL-10 found downregulated both in vivo and in vitro. However, the combination of Amlexanox and Forskolin modulated adaptive inflammatory responses and also maintained proper cardiac morphology and function. The single therapies of neither Amlexanox nor Forskolin were able to attain the aforementioned with much efficacy as their combination therapy. Conclusion: The combination therapy of ALX and FSK has the therapeutic potential of preventing the occurrence of pathological cardiac hypertrophy during CCS by modulating adaptive inflammatory responses while maintaining normal cardiac function.

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“…Stress can influence the level of circulating catecholamine, which stimulates ß-adrenergic receptor (ß-AR) and triggers diverse intracellular pathways 16 . The chronic secretion and circulation of catecholamine to produce physiological responses when they are not required may result in pathological consequences in cardiac tissue, drastically affecting cardiac function 17,18 . The stimulation of ß-ARs activates adenylyl cyclase (AC) by coupling with Gsα.…”

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confidence: 99%

Effects of occlusal disharmony on susceptibility to atrial fibrillation in mice

Suyama

Yagisawa

Okita

et al. 2020

Sci Rep

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Tooth loss or incorrect positioning causes occlusal disharmony. Furthermore, tooth loss and atrial fibrillation (AF) are both risk factors for ischemic stroke and coronary heart disease. Therefore, we hypothesized that occlusal disharmony-induced stress increases susceptibility to AF, and we designed the present study to test this idea in mice. Bite-opening (BO) was done by cementing a suitable appliance onto the mandibular incisor to cause occlusal disharmony by increasing the vertical height of occlusion by 0.7 mm for a period of 2 weeks. AF susceptibility, evaluated in terms of the duration of AF induced by transesophageal burst pacing, was significantly increased concomitantly with atrial remodeling, including fibrosis, myocyte apoptosis and oxidative DNA damage, in BO mice. The BO-induced atrial remodeling was associated with increased calmodulin kinase II-mediated ryanodine receptor 2 phosphorylation on serine 2814, as well as inhibition of Akt phosphorylation. However, co-treatment with propranolol, a non-selective β-blocker, ameliorated these changes in BO mice. These data suggest that improvement of occlusal disharmony by means of orthodontic treatment might be helpful in the treatment or prevention of AF. Abbreviations AF Atrial fibrillation BO Bite-opening β-AR Beta-adrenergic receptor AC Adenylyl cyclase ATP Adenosine triphosphate cAMP Cyclic adenosine monophosphate Epac Exchange protein activated by cAMP Control Control group Pro + BO BO plus propranolol treatment group NS Not significant BW Body weight ECG Electrocardiogram NE Norepinephrine TUNEL Terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-deoxyuridine triphosphate (dUTP) nick-end labeling 8-OHdG 8-Hydroxy-2′-deoxyguanosine CaMKII Calmodulin-dependent protein kinase II Ca 2+ Calcium oxidized-CaMKII Ox-CaMKII RyR2 Ryanodine receptor 2

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Pathological cardiac hypertrophy: the synergy of adenylyl cyclases inhibition in cardiac and immune cells during chronic catecholamine stress

Cited by 26 publications

References 129 publications

An MRTF-A–Sp1–PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy

An MRTF-A–Sp1–PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy

Combination of Amlexanox and Forskolin Attenuates Pathological Cardiac Hypertrophy by Subduing Maladaptive Inflammatory Response

Effects of occlusal disharmony on susceptibility to atrial fibrillation in mice

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