Abstract
The protein sarcospan (SSPN) is an integral member of the dystrophin glycoprotein complex (DGC) and has been shown important in the heart during development and periods of acute stress. In this study, ex vivo hearts obtained from WT and SSPN-deficient (SSPN-/-) mice were used to investigate the role of SSPN in protecting against arrhythmia after acute ischemia-reperfusion (IR) injury. Measurements of sinus heart rates in ex vivo hearts showed that SSPN-/- hearts trended toward slower cardiac conduction post-IR injury than WT hearts. Premature ventricular contractions (PVCs) were increased in SSPN-/- hearts post-IR injury during reperfusion. The regulation of intracellular Ca2+ was examined in Fura-2AM loaded WT and SSPN-/- cardiomyocytes. Acute beta-adrenergic stimulation of cardiomyocytes with 1 μM isoproterenol resulted in reduced sarcomere length, increased diastolic Ca2+ levels of WT but not SSPN-/- cardiomyocytes. After isoproterenol exposure changes in systolic Ca2+ levels similar between WT and SSPN-/- cardiomyocytes. Cardiomyocytes were treated with caffeine (10 mM) to deplete the sarcoplasmic reticulum (SR) Ca2+ store. It was found that WT cardiomyocytes had greater Ca2+ SR store than SSPN-/-. However, the total Ca2+ release from WT and SSPN-/- cardiomyocytes was similar. To better understand these results in context of IR injury, qRT-PCR was utilized to examine changes in Ca2+ handling genes. Overall, SSPN-/- hearts exhibited significantly increased expression of major Ca2+ handling genes suggesting compensation for perturbed Ca2+ handling dynamics. Interestingly, after acute IR injury the expression of L-type Ca2+-channel (LTCC) and phospholamban (PLN) were reduced in SSPN-/- hearts but not WT hearts. These results suggest that increased arrhythmia susceptibility in SSPN-/- hearts post-IR injury may arise from disruption of compensatory Ca2+ handling mechanisms in the SSPN-/- heart.
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