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Downregulation of sarcoplasmic reticulum Ca(2+)-ATPase during progression of left ventricular hypertrophy
1Cardiovascular Institute, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153, USA.
Insights
Reduced sarcoplasmic reticulum Ca(2+)-adenosinetriphosphatase (SERCA2) activity does not cause early myocardial relaxation delays in left ventricular hypertrophy (LVH). Early SERCA2 mRNA reduction may signal future cardiac dysfunction during LVH progression.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Left ventricular hypertrophy (LVH) can lead to impaired cardiac function and relaxation.
- The role of sarcoplasmic reticulum Ca(2+)-adenosinetriphosphatase (SERCA2) in diastolic dysfunction during LVH progression is not fully understood.
Purpose of the Study:
- To investigate the contribution of reduced SERCA2 activity to delayed myocardial relaxation in a rat model of chronic LVH.
- To correlate changes in myocardial composition with functional alterations during LVH progression.
Main Methods:
- LVH was induced in rats via abdominal aortic coarctation.
- Systolic and diastolic functions were assessed in vivo at 8 and 16 weeks post-surgery.
- Myocardial tissue was analyzed for SERCA2, myosin heavy chain (MHC) isoenzymes, and collagen levels.
Main Results:
- Prolonged myocardial relaxation was observed at 8 weeks, without changes in SERCA2 protein or collagen.
- At 16 weeks, significant decreases in LV SERCA2 protein, beta-MHC, and collagen correlated with impaired cardiac performance and elevated LVEDP.
- A marked reduction in SERCA2 mRNA occurred by 8 weeks, preceding changes in SERCA2 protein and SR Ca2+ uptake.
Conclusions:
- Downregulation of SERCA2 activity is unlikely to be the primary cause of early, subtle myocardial relaxation abnormalities in compensated LVH.
- Early reduction in SERCA2 mRNA may serve as a sensitive molecular marker for impending cardiac dysfunction during the transition from compensated LVH to heart failure.
Abstract:
To determine whether reduced sarcoplasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase (ATPase) (SERCA2) activity contributes to delayed myocardial relaxation during chronic left ventricular hypertrophy (LVH) progression, LVH was produced in rats by abdominal aortic coarctation. Systolic and diastolic functions were assessed in vivo 8 and 16 wk after surgery, and compositional alterations in LV myocardium [SERCA2 concentration, myosin heavy chain (MHC) isoenzymes, and tissue collagen] were correlated with the development of prolonged isovolumic relaxation and impaired cardiac performance over time. Myocardial relaxation was prolonged in 8-wk banded rats, despite normal isovolumic systolic function and LV end-diastolic pressure (LVEDP). No significant alterations in SERCA2 protein, beta-MHC, or fibrillar collagen levels were observed at this early time point. In contrast, LV SERCA2, beta-MHC, and fibrillar collagen concentrations were all significantly altered in 16-wk banded rats. These late compositional changes were associated with reduced cardiac performance, as manifested by a significant elevation in LVEDP (14 +/- 2 mmHg). The 34% decrease in SERCA2 protein was associated with reduced SR Ca2+ uptake and an even greater reduction (76%) in SERCA2 mRNA. SERCA2 mRNA levels were also significantly reduced to 43 +/- 10% of sham-operated rats 8 wk after banding, despite unchanged SERCA2 protein levels and normal SR Ca2+ uptake. These results argue against a significant contribution of SERCA2 downregulation to the subtle alterations in myocardial relaxation observed in compensated LVH. However, the early reduction in SERCA2 mRNA levels may serve as a molecular marker for impaired cardiac performance during the transition from compensated LVH to heart failure.