Abstract
Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term.
Highlights
Heart failure is the leading cause of death in the United States with more than 550,000 new diagnoses per year [1]
Upon aging to 20 months, the contractile or geometrical parameters, as evidenced by left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular posterior wall dimensions (LVPW), and circumferential strain remained similar between WT and I-1c mice (Table 1)
This study presents evidence that chronic increases of constitutively active inhibitor-1 (I-1c) to suppress cardiac PP1 activity and enhance PLN phosphorylation are well-tolerated through the aging process without compromising survival, increasing remodeling or eliciting arrhythmias under stress conditions
Summary
Heart failure is the leading cause of death in the United States with more than 550,000 new diagnoses per year [1]. When phospholamban is phosphorylated through either activation of protein kinase A (PKA) or calcium-calmodulin kinase II (CaMKII), the inhibition of the SERCA affinity for calcium by phospholamban is relieved [2,3,4]. De-phosphorylation of phospholamban is regulated by protein phosphatase-1 (PP1), which is itself modulated by a regulatory protein called inhibitor-1 (I-1) [5,6,7]. SERCA activity is reduced [8,9,10], which may be partially attributed to increased inhibition by dephosphorylated phospholamban [4,11,12,13]. An emerging pathway in modulating PLN activity is inhibition of protein phosphatase 1 (PP1) that is significantly elevated in heart failure. The phospholamban associated inhibitor-1/PP1 regulatory complex plays a key role in the compromised or dys-regulated Ca-cycling in failing hearts
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