CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production
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 elucid...
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2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| author | Keai Sinn Tan Dongfang Wang Ziqiang Lu Yihan Zhang Sixu Li Yue Lin Wen Tan |
| author_facet | Keai Sinn Tan Dongfang Wang Ziqiang Lu Yihan Zhang Sixu Li Yue Lin Wen Tan |
| author_sort | Keai Sinn Tan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T06:59:10Z |
| format | Article |
| id | doaj.art-b520807de96a4407abeea4eb14ae6c56 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:59:10Z |
| publishDate | 2021-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b520807de96a4407abeea4eb14ae6c562023-11-22T16:15:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122191080610.3390/ijms221910806CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy ProductionKeai Sinn Tan0Dongfang Wang1Ziqiang Lu2Yihan Zhang3Sixu Li4Yue Lin5Wen Tan6College of Pharmacy, Jinan University, Guangzhou 510632, ChinaCollege of Pharmacy, Jinan University, Guangzhou 510632, ChinaPost-Doctoral Innovation Base, Jinan University Affiliation, Yuanzhi Health Technology Co., Ltd., Hengqin New District, Zhuhai, Guangdong 51900, ChinaPost-Doctoral Innovation Base, Jinan University Affiliation, Yuanzhi Health Technology Co., Ltd., Hengqin New District, Zhuhai, Guangdong 51900, ChinaPost-Doctoral Innovation Base, Jinan University Affiliation, Yuanzhi Health Technology Co., Ltd., Hengqin New District, Zhuhai, Guangdong 51900, ChinaPost-Doctoral Innovation Base, Jinan University Affiliation, Yuanzhi Health Technology Co., Ltd., Hengqin New District, Zhuhai, Guangdong 51900, ChinaPost-Doctoral Innovation Base, Jinan University Affiliation, Yuanzhi Health Technology Co., Ltd., Hengqin New District, Zhuhai, Guangdong 51900, ChinaHeart 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.https://www.mdpi.com/1422-0067/22/19/10806CNPaseheart failure animal modelzebrafishCRISPR-Cas9mitochondrial energy production |
| spellingShingle | Keai Sinn Tan Dongfang Wang Ziqiang Lu Yihan Zhang Sixu Li Yue Lin Wen Tan 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 CNPase heart failure animal model zebrafish CRISPR-Cas9 mitochondrial energy production |
| title | CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production |
| title_full | CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production |
| title_fullStr | CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production |
| title_full_unstemmed | CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production |
| title_short | CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production |
| title_sort | cnpase a 2 3 cyclic nucleotide 3 phosphodiesterase as a therapeutic target to attenuate cardiac hypertrophy by enhancing mitochondrial energy production |
| topic | CNPase heart failure animal model zebrafish CRISPR-Cas9 mitochondrial energy production |
| url | https://www.mdpi.com/1422-0067/22/19/10806 |
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