Abstract
Severe dysfunction in cardiac muscle intracellular Ca2+ handling is a common pathway underlying heart failure. Here we used an inducible genetic model of severe Ca2+ cycling dysfunction by the targeted temporal gene ablation of the cardiac Ca2+ ATPase, SERCA2, in otherwise normal adult mice. In this model, in vivo heart performance was minimally affected initially, even though Serca2a protein was markedly reduced. The mechanism underlying the sustained in vivo heart performance in the weeks prior to complete heart pump failure and death is not clear and is important to understand. Studies were primarily focused on understanding how in vivo diastolic function could be relatively normal under conditions of marked Serca2a deficiency. Interestingly, data show increased cardiac troponin I (cTnI) serine 23/24 phosphorylation content in hearts upon Serca2a ablation in vivo. We report that hearts isolated from the Serca2-deficient mice retained near normal heart pump functional responses to β-adrenergic stimulation. Unexpectedly, using genetic complementation models, in concert with inducible Serca2 ablation, data show that Serca2a-deficient hearts that also lacked the central β-adrenergic signaling–dependent Serca2a negative regulator, phospholamban (PLN), had severe diastolic dysfunction that could still be corrected by β-adrenergic stimulation. Notably, integrating a serines 23/24–to–alanine PKA-refractory sarcomere incorporated cTnI molecular switch complex in mice deficient in Serca2 showed blunting of β-adrenergic stimulation–mediated enhanced diastolic heart performance. Taken together, these data provide evidence of a compensatory regulatory role of the myofilaments as a critical physiological bridging mechanism to aid in preserving heart diastolic performance in failing hearts with severe Ca2+ handling deficits.
Authors
Frazer I. Heinis, Brian R. Thompson, Rishi Gulati, Matthew Wheelwright, Joseph M. Metzger
Figure 2
Effects of CPA chemical inhibition of the Serca2a ATPase in hearts after Serca2 gene ablation.
