Is reduced SERCA2a expression detrimental or beneficial to postischemic cardiac function and injury? Evidence from heterozygous SERCA2a knockout mice.

Abstract

Recent studies have demonstrated that increased expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) 2a improves myocardial contractility and Ca2+ handling at baseline and in disease conditions, including myocardial ischemia-reperfusion (I/R). Conversely, it has also been reported that pharmacological inhibition of SERCA might improve postischemic function in stunned hearts or in isolated myocardium following I/R. The goal of this study was to test how decreases in SERCA pump level/activity affect cardiac function following I/R. To address this question, we used a heterozygous SERCA2a knockout (SERCA2a+/-) mouse model with decreased SERCA pump levels and studied the effect of myocardial stunning (20-min ischemia followed by reperfusion) and infarction (30-min ischemia followed by reperfusion) following 60-min reperfusion. Our results demonstrate that postischemic myocardial relaxation was significantly impaired in SERCA2a+/- hearts with both stunning and infarction protocols. Interestingly, postischemic recovery of contractile function was comparable in SERCA2a+/- and wild-type hearts subjected to stunning. In contrast, following 30-min ischemia, postischemic contractile function was reduced in SERCA2a+/- hearts with significantly larger infarction. Rhod-2 spectrofluorometry revealed significantly higher diastolic intracellular Ca2+ in SERCA2a+/- hearts compared with wild-type hearts. Both at 30-min ischemia and 2-min reperfusion, intracellular Ca2+ levels were significantly higher in SERCA2a+/- hearts. Electron paramagnetic resonance spin trapping showed a similar extent of postischemic free-radical generation in both strains. These data provide direct evidence that functional SERCA2a level, independent of oxidative stress, is crucial for postischemic myocardial function and salvage during I/R.

• Authors: M A Hassan Talukder, Anuradha Kalyanasundaram, Li Zuo, Murugesan Velayutham, Yoshinori Nishijima, Muthu Periasamy, Jay L Zweier
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 294 Issue 3 Pg. H1426-34 (Mar 2008) ISSN: 0363-6135 [Print] United States
• PMID: 18203847 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Fluorescent Dyes
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Echocardiography
• Electron Spin Resonance Spectroscopy
• Fluorescent Dyes
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Infarction (genetics, pathology)
• Myocardial Reperfusion Injury (enzymology, genetics, pathology)
• Myocardial Stunning (physiopathology)
• Myocardium (metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (biosynthesis, genetics)
• Ventricular Function, Left (physiology)