Abstract
HNO donors enhance cardiac inotropy by increasing SR Ca2+ re-uptake/release. Given its thiophylic nature, HNO likely modifyies critical cysteine residues in E-C coupling proteins. Phospholamban (PLN) is a potential target for HNO, and its genetic removal or mutation of PLN cysteines should abolish/blunt HNO cardiac effects. Cardiomyocytes were isolated from PLN knockout (PLN-/-) and wildtype (WT) mice, field-stimulated and assessed for Ca2+ transients and sarcomere shortening (SS). HNO effects on the SR-Ca2+ATPase (SERCA2a) were evaluated by isolating SR vesicles from PLN-/- and WT mice and measuring Ca2+ uptake by stopped-flow mixing. Dephosphorylation of SERCA2a (a measure of E2P hydrolysis) was investigated in ER microsomes from Sf21 insect cells expressing SERCA2a±PLN (WT or Cys 36-41-46->Ala mutant). PLN-/- myocytes showed enhanced myocyte contraction and a blunted response to isoproterenol. When challenged with the HNO donor Angeli's salt (AS, 0.5 mM), Ca2+ transient amplitude (-15±5 vs 17±7% in WT, p Ala PLN (0.21 vs 0.18 s-1). We conclude that PLN is essential for the HNO-mediated increase in Ca2+ uptake by SERCA2a, and that modification of PLN thiols is central to this modulation. Enhancing Ca2+ uptake by HNO may benefit heart failure patients that often display depressed SR function.
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