Research Advances in Kinase Enzymes and Inhibitors for Cardiovascular Disease Treatment

Shahin, Rand; Shaheen, Omar; El‐Dahiyat, Faris; Habash, Maha; Saffour, Sana

doi:10.4155/fsoa-2017-0010

Cited by 16 publications

(5 citation statements)

References 92 publications

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“…Different isoenzymes of PKC may play different roles in angiogenesis in diverse stem cell types under various conditions. Future studies are indicated to clarify the potential impacts of PKC isoenzymes in cardiovascular disease [30].…”

Section: Discussionmentioning

confidence: 99%

Phorbol ester-induced angiogenesis of endothelial progenitor cells: The role of NADPH oxidase-mediated, redox-related matrix metalloproteinase pathways

Chang²,

Leu

et al. 2019

PLoS ONE

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Endothelial progenitor cells (EPCs) may contribute to ischemia-induced angiogenesis in atherosclerotic diseases. The protein kinase C (PKC) family is involved in the regulation of angiogenesis, however the role of PKCα in EPCs during angiogenesis is unclear. The aim of this study was to evaluate the role of PKCα in EPCs during angiogenesis. Phorbol-12-myristate-13-acetate (PMA), a PKCα activator, significantly increased the activity and expression of matrix metalloproteinases (MMP) -2 and -9 in human (late outgrowth) EPCs in vitro. The MMPs promoted the migratory function and vascular formation of EPCs, which then contributed to neovascularization in a mouse hindlimb-ischemia model. Reactive oxygen species derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enhanced the expression of MMPs to increase the bioactivity of EPCs during angiogenesis. The mitogen-activated protein kinase (MAPK) signal pathway was associated with the activation of NADPH oxidase. PMA extensively activated the extracellular signal–regulated kinase (Erk) signal pathway to increase the expression of MMP-9. PMA also activated the p38, Erk, and c-Jun N-terminal kinase signal pathways to increase the expression of MMP-2. PMA-stimulated EPCs enhanced neovascularization in a mouse model of hindlimb ischemia via nuclear factor-κB translocation to up-regulation of the expression of MMP-2 and MMP-9. PMA could activate PKCα and promote the angiogenesis capacity of human EPCs via NADPH oxidase-mediated, redox-related, MMP-2 and MMP-9 pathways. The PKCα-activated, NADPH oxidase-mediated, redox-related MMP pathways could contribute to the function of human EPCs for ischemia-induced neovascularization, which may provide novel insights into the potential modification of EPCs for therapeutic angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Phorbol ester-induced angiogenesis of endothelial progenitor cells: The role of NADPH oxidase-mediated, redox-related matrix metalloproteinase pathways

Chang²,

Leu

et al. 2019

PLoS ONE

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“…Mitochondria are the predominant cellular source of ROS and energy production. If mitochondria become damaged, their oxidative phosphory-lation capacity is reduced, which can subsequently result in excessive ROS production and abnormal calcium homeostasis, thereby promoting cardiomyocyte necroptosis [46][47][48].…”

Section: Discussionmentioning

confidence: 99%

Ca2+/Calmodulin-Dependent Protein Kinase II Regulation by Inhibitor of RIPK3 Protects against Cardiac Hypertrophy

Zhang

Qian

Cao

et al. 2022

Oxidative Medicine and Cellular Longevity

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The activity of Ca2+/calmodulin-dependent protein kinase II δ (CaMKII δ) is central to the mechanisms of cardiovascular diseases. Receptor-interacting protein kinase 3- (RIPK3-) mediated necroptosis has been reported to contribute to cardiac dysfunction. However, the potential protective role of inhibition of RIPK3, a regulator of CaMKII, on cardiac hypertrophy remains unclear. The present study is aimed at investigating how the RIPK3 inhibitor GSK’872 regulates CaMKII activity and exploring its effect on hypertrophic cardiomyopathy (HCM). Wild-type (WT) and RIPK3 gene knockout (RIPK3-/-) mice were implanted subcutaneously with Alzet miniosmotic pumps (200 μL) and perfused with angiotensin II (AMP-AngII) to induce cardiac hypertrophy. After WT mice were induced by AngII for 72 hours, they were injected with GSK’872 with an intraperitoneal (IP) dose of 6 mg/kg once a day for two weeks. After this, they were physiologically examined for Echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK3 expression, mixed lineage kinase domain-like protein (MLKL) phosphorylation, and mitochondrial ultrastructure. The results indicated that deletion of the RIPK3 gene or administration of GSK’872 could reduce CaMKII activity, alleviate oxidative stress, reduce necroptosis, and reverse myocardial injury and cardiac dysfunction caused by AngII-induced cardiac hypertrophy in mice. The present study demonstrated that CaMKII activation and necroptosis augment cardiac hypertrophy in a RIPK3-dependent manner, which may provide therapeutic strategies for HCM. RIPK3 inhibitor GSK’872 has a protective effect on cardiac hypertrophy and could be an efficacious targeted medicine for HCM in clinical treatment.

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“…There are a myriad of kinases and phosphatases regulated by cytosolic Ca 2+ signals, which are sensitive to Ca 2+ location, size, and frequency 14. One such Ca 2+ sensor, Ca 2+ /calmodulin-dependent enzyme (CAMK), controls cardiomyocyte growth, differentiation, and development, which are also important factors in the pathophysiology of various cardiac diseases 15, 16. The other, calcineurin, has recently been demonstrated to have beneficial effects on myocardial hypertrophy and ventricular function 17.…”

Section: Pgc-1 Signaling Networkmentioning

confidence: 99%

Blossoming 20: The Energetic Regulator's Birthday Unveils its Versatility in Cardiac Diseases

Lv¹,

Deng²,

Jiang³

et al. 2019

Theranostics

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The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) was first identified in 1998 as a PGC-1 family member that regulates adaptive thermogenesis and mitochondrial function following cold exposure in brown adipose tissue. The PGC-1 family has drawn widespread attention over the past two decades as the energetic regulator. We recently summarized a review regarding PGC-1 signaling pathway and its mechanisms in cardiac metabolism. In this review, we elaborate upon the PGC-1 signaling network and highlight the recent progress of its versatile roles in cardiac diseases, including myocardial hypertrophy, peripartum and diabetic cardiomyopathy, and heart failure. The information reviewed here may be useful in future studies, which may increase the potential of this energetic regulator as a therapeutic target.

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Research Advances in Kinase Enzymes and Inhibitors for Cardiovascular Disease Treatment

Cited by 16 publications

References 92 publications

Phorbol ester-induced angiogenesis of endothelial progenitor cells: The role of NADPH oxidase-mediated, redox-related matrix metalloproteinase pathways

Phorbol ester-induced angiogenesis of endothelial progenitor cells: The role of NADPH oxidase-mediated, redox-related matrix metalloproteinase pathways

Ca2+/Calmodulin-Dependent Protein Kinase II Regulation by Inhibitor of RIPK3 Protects against Cardiac Hypertrophy

Blossoming 20: The Energetic Regulator's Birthday Unveils its Versatility in Cardiac Diseases

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