A Chymase Inhibitory RNA Aptamer Improves Cardiac Function and Survival after Myocardial Infarction

Jin, Denan; Nonaka, Y.; Yamazaki, Satoko; Fujiwara, Masatoshi; Nakamura, Yoshikazu

doi:10.1016/j.omtn.2018.11.001

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…Interestingly, combined inhibition of both chymase and ACE was superior to ACE-I alone, as was evident by improved cardiac function and cardiac remodeling in rodents ( 58 ). In line with these findings, clinical studies demonstrated that an inhibitor of chymase-specific RNA aptamer improved cardiac function in patients following myocardial infarction ( 72 ).…”

Section: Chymase and Covid-19mentioning

confidence: 74%

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

Abassi

Skorecki

Hamo-Giladi

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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The unique clinical features of COVID-19 disease present a formidable challenge in the understanding of its pathogenesis. Within a very short time, our knowledge regarding basic physiologic pathways that participate in SARS CoV-2 invasion and subsequent organ damage have been dramatically expanded. In particular, we now better understand the complexity of the renin-angiotensin-aldosterone system (RAAS) and the important role of angiotensin converting enzyme (ACE)-2 in viral binding. Furthermore, the critical role of its major product, angiotensin (Ang) 1-7, in maintaining microcirculatory balance and in the control of activated pro-inflammatory and pro-coagulant pathways, generated in this disease, have been clarified. The kalikrein-bradykinin (BK) system and chymase are intensively interwoven with RAAS through many pathways with complex reciprocal interactions. Yet, so far, very little attention has been paid to a possible role of these physiologic pathways in the pathogenesis of COVID-19 disease, even though BK and chymase exert many physiologic changes characteristic to this disorder. Herein we outline the current knowledge regarding the reciprocal interactions of RAAS, BK and chymase that are probably turned-on in COVID-19 disease and participate in its clinical features. Interventions affecting these systems, such as the inhibition of chymase or blocking BKB1R/BKB2R might be explored as potential novel therapeutic strategies in this devastating disorder.

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Section: Chymase and Covid-19mentioning

confidence: 74%

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

Abassi

Skorecki

Hamo-Giladi

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…We also observed that the specific chymase inhibitor TY-51469 showed a reduction of mast cell and MMCP-4-positive cell numbers. Numerous studies have demonstrated that chymase inhibitors can reduce mast cell numbers in various experimental models [ 38 , 39 , 40 , 41 ]. Chymase is known to enzymatically cleave the inactive membrane-bound form of stem cell factor (SCF) to the active form of SCF, and the activated SCF stimulates the development and proliferation of mast cells, resulting in increased mast cell numbers [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice

Terai

Jin

Watase

et al. 2020

IJMS

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Chymase has several functions, such as angiotensin II formation, which can promote diabetic kidney disease (DKD). In this study, we evaluated the effect of the chymase inhibitor TY-51469 on DKD in diabetic db/db mice. Diabetic mice were administered TY-51469 (10 mg/kg/day) or placebo for 4 weeks. No significant difference was observed in body weight and fasting blood glucose between TY-51469- and placebo-treated groups. However, a significant reduction in urinary albumin/creatinine ratio was observed in the TY-51469-treated group compared with the placebo-treated group. In the renal extract, chymase activity was significantly higher in placebo-treated mice than in non-diabetic db/m mice, but it was reduced by treatment with TY-51469. Both NADPH oxidase 4 expression and the oxidative stress marker malondialdehyde were significantly augmented in the placebo-treated group, but they were attenuated in the TY-51469-treated group. Significant increases of tumor necrosis factor-α and transforming growth factor-β mRNA levels in the placebo-treated group were significantly reduced by treatment with TY-51469. Furthermore, the expression of nephrin, which is a podocyte-specific protein, was significantly reduced in the placebo-treated group, but it was restored in the TY-51469-treated group. These findings demonstrated that chymase inhibition reduced albuminuria via attenuation of podocyte injury by oxidative stress.

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“…Furthermore, the aptamer also blocked tumor cell dissemination in mice, providing a new insight for miRNA-based therapeutic development. In a similar study, Jin et al (2019) developed an RNA aptamer (HA28) towards chymase, which plays an essential role in the regulation of Ang II in cardiovascular tissues [ 71 ]. The effect of HA28 aptamer was evaluated on the cardiovascular tissues, after myocardial infarction.…”

Section: Aptamers As Therapeutic Agentsmentioning

confidence: 99%

Current Perspectives on Aptamers as Diagnostic Tools and Therapeutic Agents

2020

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Aptamers are synthetic single-stranded DNA or RNA sequences selected from combinatorial oligonucleotide libraries through the well-known in vitro selection and iteration process, SELEX. The last three decades have witnessed a sudden boom in aptamer research, owing to their unique characteristics, like high specificity and binding affinity, low immunogenicity and toxicity, and ease in synthesis with negligible batch-to-batch variation. Aptamers can specifically bind to the targets ranging from small molecules to complex structures, making them suitable for a myriad of diagnostic and therapeutic applications. In analytical scenarios, aptamers are used as molecular probes instead of antibodies. They have the potential in the detection of biomarkers, microorganisms, viral agents, environmental pollutants, or pathogens. For therapeutic purposes, aptamers can be further engineered with chemical stabilization and modification techniques, thus expanding their serum half-life and shelf life. A vast number of antagonistic aptamers or aptamer-based conjugates have been discovered so far through the in vitro selection procedure. However, the aptamers face several challenges for its successful clinical translation, and only particular aptamers have reached the marketplace so far. Aptamer research is still in a growing stage, and a deeper understanding of nucleic acid chemistry, target interaction, tissue distribution, and pharmacokinetics is required. In this review, we discussed aptamers in the current diagnostics and theranostics applications, while addressing the challenges associated with them. The report also sheds light on the implementation of aptamer conjugates for diagnostic purposes and, finally, the therapeutic aptamers under clinical investigation, challenges therein, and their future directions.

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A Chymase Inhibitory RNA Aptamer Improves Cardiac Function and Survival after Myocardial Infarction

Cited by 9 publications

References 34 publications

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice

Current Perspectives on Aptamers as Diagnostic Tools and Therapeutic Agents

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