Protein Kinase A Is a Master Regulator of Physiological and Pathological Cardiac Hypertrophy
BACKGROUND: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear.
METHODS: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice.
RESULTS: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3β signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival.
CONCLUSIONS: Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:134 |
|---|---|
| Enthalten in: |
Circulation research - 134(2024), 4 vom: 16. Feb., Seite 393-410 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bai, Yingyu [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 19.02.2024 Date Revised 14.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1161/CIRCRESAHA.123.322729 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM367655276 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM367655276 | ||
| 003 | DE-627 | ||
| 005 | 20240314234949.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240126s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/CIRCRESAHA.123.322729 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1329.xml |
| 035 | |a (DE-627)NLM367655276 | ||
| 035 | |a (NLM)38275112 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bai, Yingyu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Protein Kinase A Is a Master Regulator of Physiological and Pathological Cardiac Hypertrophy |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 19.02.2024 | ||
| 500 | |a Date Revised 14.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear | ||
| 520 | |a METHODS: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice | ||
| 520 | |a RESULTS: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3β signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival | ||
| 520 | |a CONCLUSIONS: Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cyclic AMP-dependent protein kinases | |
| 650 | 4 | |a heart | |
| 650 | 4 | |a hypertrophy | |
| 650 | 4 | |a mechanistic target of rapamycin complex 1 | |
| 650 | 4 | |a proteolysis | |
| 650 | 7 | |a Proteasome Endopeptidase Complex |2 NLM | |
| 650 | 7 | |a EC 3.4.25.1 |2 NLM | |
| 650 | 7 | |a Cyclic AMP-Dependent Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.11 |2 NLM | |
| 650 | 7 | |a Glycogen Synthase Kinase 3 beta |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 700 | 1 | |a Zhang, Xiaoying |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Chong |e verfasserin |4 aut | |
| 700 | 1 | |a Ai, Xiaojie |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Mingxin |e verfasserin |4 aut | |
| 700 | 1 | |a Szeto, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Erhe |e verfasserin |4 aut | |
| 700 | 1 | |a Hua, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Mingxing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xuejun |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yongjie |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Guowei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Junping |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Weidong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Lili |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xueyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Houser, Steven R |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xiongwen |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Circulation research |d 1953 |g 134(2024), 4 vom: 16. Feb., Seite 393-410 |w (DE-627)NLM000001910 |x 1524-4571 |7 nnns |
| 773 | 1 | 8 | |g volume:134 |g year:2024 |g number:4 |g day:16 |g month:02 |g pages:393-410 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1161/CIRCRESAHA.123.322729 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 134 |j 2024 |e 4 |b 16 |c 02 |h 393-410 | ||