Loss of the AE3 Cl-/HCO3- exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart
Cl-/HCO3- exchangers are expressed abundantly in cardiac muscle, suggesting that HCO3- extrusion serves an important function in heart. Mice lacking Anion Exchanger Isoform 3 (AE3), a major cardiac Cl-/HCO3- exchanger, appear healthy, but loss of AE3 causes decompensation in a hypertrophic cardiomyo...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2013-12-01
|
| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphys.2013.00399/full |
| _version_ | 1818838497387085824 |
|---|---|
| author | Vikram ePrasad John N Lorenz Valerie M Lasko Michelle L Nieman Nabeel J Al Moamen Gary E Shull |
| author_facet | Vikram ePrasad John N Lorenz Valerie M Lasko Michelle L Nieman Nabeel J Al Moamen Gary E Shull |
| author_sort | Vikram ePrasad |
| collection | DOAJ |
| description | Cl-/HCO3- exchangers are expressed abundantly in cardiac muscle, suggesting that HCO3- extrusion serves an important function in heart. Mice lacking Anion Exchanger Isoform 3 (AE3), a major cardiac Cl-/HCO3- exchanger, appear healthy, but loss of AE3 causes decompensation in a hypertrophic cardiomyopathy (HCM) model. Using intra-ventricular pressure analysis, in vivo pacing, and molecular studies we identified physiological and biochemical changes caused by loss of AE3 that may contribute to decompensation in HCM. AE3-null mice had normal cardiac contractility under basal conditions and after -adrenergic stimulation, but pacing of hearts revealed that frequency-dependent inotropy was blunted, suggesting that AE3-mediated HCO3- extrusion is required for a robust force-frequency response (FFR) during acute biomechanical stress in vivo. Modest changes in expression of proteins that affect Ca2+-handling were observed, but Ca2+-transient analysis of AE3-null myocytes showed normal twitch-amplitude and Ca2+-clearance. Phosphorylation and expression of several proteins implicated in HCM and FFR, including phospholamban, myosin binding protein C, and troponin I were not altered in hearts of paced AE3-null mice; however, phosphorylation of Akt, which plays a central role in mechanosensory signaling, was significantly higher in paced AE3-null hearts than in wild-type controls and phosphorylation of AMPK, which is affected by Akt and is involved in energy metabolism and some cases of HCM, was reduced. These data show loss of AE3 leads to impaired rate-dependent inotropy, appears to affect mechanical stress-responsive signaling, and reduces activation of AMPK, which may contribute to decompensation in heart failure. |
| first_indexed | 2024-12-19T03:39:20Z |
| format | Article |
| id | doaj.art-23a775aa6bbf4143b7558a259360bfe6 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-19T03:39:20Z |
| publishDate | 2013-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-23a775aa6bbf4143b7558a259360bfe62022-12-21T20:37:17ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2013-12-01410.3389/fphys.2013.0039969917Loss of the AE3 Cl-/HCO3- exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heartVikram ePrasad0John N Lorenz1Valerie M Lasko2Michelle L Nieman3Nabeel J Al Moamen4Gary E Shull5University of Cincinnati College of MedicineUniversity of Cincinnati College of MedicineUniversity of Cincinnati College of MedicineUniversity of Cincinnati College of MedicineUniversity of Cincinnati College of MedicineUniversity of Cincinnati College of MedicineCl-/HCO3- exchangers are expressed abundantly in cardiac muscle, suggesting that HCO3- extrusion serves an important function in heart. Mice lacking Anion Exchanger Isoform 3 (AE3), a major cardiac Cl-/HCO3- exchanger, appear healthy, but loss of AE3 causes decompensation in a hypertrophic cardiomyopathy (HCM) model. Using intra-ventricular pressure analysis, in vivo pacing, and molecular studies we identified physiological and biochemical changes caused by loss of AE3 that may contribute to decompensation in HCM. AE3-null mice had normal cardiac contractility under basal conditions and after -adrenergic stimulation, but pacing of hearts revealed that frequency-dependent inotropy was blunted, suggesting that AE3-mediated HCO3- extrusion is required for a robust force-frequency response (FFR) during acute biomechanical stress in vivo. Modest changes in expression of proteins that affect Ca2+-handling were observed, but Ca2+-transient analysis of AE3-null myocytes showed normal twitch-amplitude and Ca2+-clearance. Phosphorylation and expression of several proteins implicated in HCM and FFR, including phospholamban, myosin binding protein C, and troponin I were not altered in hearts of paced AE3-null mice; however, phosphorylation of Akt, which plays a central role in mechanosensory signaling, was significantly higher in paced AE3-null hearts than in wild-type controls and phosphorylation of AMPK, which is affected by Akt and is involved in energy metabolism and some cases of HCM, was reduced. These data show loss of AE3 leads to impaired rate-dependent inotropy, appears to affect mechanical stress-responsive signaling, and reduces activation of AMPK, which may contribute to decompensation in heart failure.http://journal.frontiersin.org/Journal/10.3389/fphys.2013.00399/fullHypertrophyPKBprotein kinase BNBCe1Slc4a3SERCA2 |
| spellingShingle | Vikram ePrasad John N Lorenz Valerie M Lasko Michelle L Nieman Nabeel J Al Moamen Gary E Shull Loss of the AE3 Cl-/HCO3- exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart Frontiers in Physiology Hypertrophy PKB protein kinase B NBCe1 Slc4a3 SERCA2 |
| title | Loss of the AE3 Cl-/HCO3- exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart |
| title_full | Loss of the AE3 Cl-/HCO3- exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart |
| title_fullStr | Loss of the AE3 Cl-/HCO3- exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart |
| title_full_unstemmed | Loss of the AE3 Cl-/HCO3- exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart |
| title_short | Loss of the AE3 Cl-/HCO3- exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart |
| title_sort | loss of the ae3 cl hco3 exchanger in mice affects rate dependent inotropy and stress related akt signaling in heart |
| topic | Hypertrophy PKB protein kinase B NBCe1 Slc4a3 SERCA2 |
| url | http://journal.frontiersin.org/Journal/10.3389/fphys.2013.00399/full |
| work_keys_str_mv | AT vikrameprasad lossoftheae3clhco3exchangerinmiceaffectsratedependentinotropyandstressrelatedaktsignalinginheart AT johnnlorenz lossoftheae3clhco3exchangerinmiceaffectsratedependentinotropyandstressrelatedaktsignalinginheart AT valeriemlasko lossoftheae3clhco3exchangerinmiceaffectsratedependentinotropyandstressrelatedaktsignalinginheart AT michellelnieman lossoftheae3clhco3exchangerinmiceaffectsratedependentinotropyandstressrelatedaktsignalinginheart AT nabeeljalmoamen lossoftheae3clhco3exchangerinmiceaffectsratedependentinotropyandstressrelatedaktsignalinginheart AT garyeshull lossoftheae3clhco3exchangerinmiceaffectsratedependentinotropyandstressrelatedaktsignalinginheart |