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1 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
2 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Medical and Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD, USA
3 Department of Medical and Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD, USA
4 Department of Medicine, University of California, at San Diego, La Jolla, CA, USA
* To whom correspondence should be addressed. E-mail: yibinwang{at}umnet.ucla.edu.
Small G-protein Ras mediated signaling pathway has been implicated in the development of hypertrophy and diastolic dysfunction in heart. Earlier cellular studies have suggested that Ras pathway is responsible for reduced L-type calcium channel current and SR calcium uptake associated with sarcomere disorganization in neonatal cardiomyocytes. In this study, we investigated the in vivo effects of Ras activation on cellular calcium handling and sarcomere organization in adult ventricular myocytes using a newly established transgenic mouse model with targeted expression of H-RasV12 mutant. The transgenic hearts expressing activated Ras developed significant hypertrophy and postnatal lethal heart failure. In adult ventricular myocytes isolated from the transgenic hearts, calcium transient was significantly depressed but membrane L-type calcium current was unchanged comparing to control littermates. The expression of sarcoplasmic reticulum calcium ATPase (SERCA2a) and phospholamban (PLB) were all significantly reduced at mRNA levels. The amount of SERCA2a protein was also modestly reduced. However, the expression of PLB protein and gross sarcomere organization remained unchanged in the hypertrophic Ras hearts, while Ser-16 phosphorylation of PLB was dramatically inhibited in the Ras transgenic hearts comparing to controls. Hypo-osphorylation of PLB was also associated with significant induction of protein phosphatase 1 expression. Therefore, our results from this in vivo model system suggest that Ras induced contractile defects does not involve decreased L-type calcium channel activities or disruption of sarcomere structure. Rather, suppressed SR calcium uptake due to reduced SERCA2a expression and hypo-phosphorylation of phospholamban due to changes in protein phosphatase expression may play important roles in the diastolic dysfunction of Ras mediated hypertrophic cardiomyopathy.
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