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CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production

by 1,2,†, 1,2,†, 2, 2, 2, 2 and 2,3,*
1
College of Pharmacy, Jinan University, Guangzhou 510632, China
2
Post-Doctoral Innovation Base, Jinan University Affiliation, Yuanzhi Health Technology Co., Ltd., Hengqin New District, Zhuhai, Guangdong 51900, China
3
Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Malaysia
*
Author to whom correspondence should be addressed.
These authors contributed equally to the study.
Academic Editors: Jacek Z. Kubiak and Malgorzata Kloc
Int. J. Mol. Sci. 2021, 22(19), 10806; https://doi.org/10.3390/ijms221910806
Received: 27 August 2021 / Revised: 29 September 2021 / Accepted: 29 September 2021 / Published: 6 October 2021
Heart failure is the end-stage of all cardiovascular diseases with a ~25% 5-year survival rate, and insufficient mitochondrial energy production to meet myocardial demand is the hallmark of heart failure. Mitochondrial components involved in the regulation of ATP production remain to be fully elucidated. Recently, roles of 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) in the pathophysiological processes of heart diseases have emerged, implicated by evidence that mitochondrial CNPase proteins are associated with mitochondrial integrity under metabolic stress. In this study, a zebrafish heart failure model was established, by employing antisense morpholino oligonucleotides and the CRISPR-Cas9 gene-editing system, which recapitulates heart failure phenotypes including heart dysfunction, pericardial edema, ventricular enlargement, bradycardia, and premature death. The translational implications of CNPase in the pathophysiological process of heart failure were tested in a pressure overload-induced heart hypertrophy model, which was carried out in rats through transverse abdominal aorta constriction (TAAC). AAV9-mediated myocardial delivery of CNPase mitigated the hypertrophic response through the specific hydrolysis of 2′-3′-cyclic nucleotides, supported by the decrease of cardiac hypertrophy and fibrosis, the integrity of mitochondrial ultrastructure, and indicators of heart contractility in the AAV9-TAAC group. Finally, the biometrics of a mitochondrial respiration assay carried out on a Seahorse cellular energy analyzer demonstrated that CNPase protects mitochondrial respiration and ATP production from AngII-induced metabolic stress. In summary, this study provides mechanistic insights into CNPase-2′,3′-cyclic nucleotide metabolism that protects the heart from energy starvation and suggests novel therapeutic approaches to treat heart failure by targeting CNPase activity. View Full-Text
Keywords: CNPase; heart failure animal model; zebrafish; CRISPR-Cas9; mitochondrial energy production CNPase; heart failure animal model; zebrafish; CRISPR-Cas9; mitochondrial energy production
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MDPI and ACS Style

Tan, K.S.; Wang, D.; Lu, Z.; Zhang, Y.; Li, S.; Lin, Y.; Tan, W. CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production. Int. J. Mol. Sci. 2021, 22, 10806. https://doi.org/10.3390/ijms221910806

AMA Style

Tan KS, Wang D, Lu Z, Zhang Y, Li S, Lin Y, Tan W. CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production. International Journal of Molecular Sciences. 2021; 22(19):10806. https://doi.org/10.3390/ijms221910806

Chicago/Turabian Style

Tan, Keai S., Dongfang Wang, Ziqiang Lu, Yihan Zhang, Sixu Li, Yue Lin, and Wen Tan. 2021. "CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production" International Journal of Molecular Sciences 22, no. 19: 10806. https://doi.org/10.3390/ijms221910806

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