Cardiac-specific deletion of protein phosphatase 1β promotes increased myofilament protein phosphorylation and contractile alterations. (October 2015)

• Record Type: Journal Article
• Authors: Liu, Ruijie; Correll, Robert N.; Davis, Jennifer; Vagnozzi, Ronald J.; York, Allen J.; Sargent, Michelle A.; Nairn, Angus C.; Molkentin, Jeffery D.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 87(2015:Oct.)
• Page Start: 204
• Page End: 213
• Publication Date: 2015-10
• Subjects: αMHC α-myosin heavy chain -- cMyBPC cardiac myosin binding protein C -- FS fractional shortening -- I-1 inhibitor 1 -- I-2 inhibitor 2 -- IP intraperitoneal -- fl loxP site -- LV left ventricle -- MLC2V myosin light chain 2 V -- MLCK myosin light chain kinase -- PKA protein kinase A -- PP1 protein phosphatase 1 -- PLN phospholamban -- SERCA sarcoplasmic/endoplasmic reticulum Ca2 + ATPase -- shRNA short hairpin RNA -- SR sarcoplasmic reticulum; Protein phosphatase 1 -- Myofilament protein -- Contractility -- Heart failure; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.08.018
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: There are 3 protein phosphatase 1 (PP1) catalytic isoforms (α, β and γ) encoded within the mammalian genome. These 3 gene products share ~ 90% amino acid homology within their catalytic domains but each has unique N- and C-termini that likely underlie distinctive subcellular localization or functionality. In this study, we assessed the effect associated with the loss of each PP1 isoform in the heart using a conditional Cre-loxP targeting approach in mice. Ppp1ca-loxP, Ppp1cb-loxP and Ppp1cc-loxP alleles were crossed with either an Nkx2.5-Cre knock-in containing allele for early embryonic deletion or a tamoxifen inducible α-myosin heavy chain (αMHC)-MerCreMer transgene for adult and cardiac-specific deletion. We determined that while deletion of Ppp1ca (PP1α) or Ppp1cc (PP1γ) had little effect on the whole heart, deletion of Ppp1cb (PP1β) resulted in concentric remodeling of the heart, interstitial fibrosis and contractile dysregulation, using either the embryonic or adult-specific Cre-expressing alleles. However, myocytes isolated from Ppp1cb deleted hearts surprisingly showed enhanced contractility. Mechanistically we found that deletion of any of the 3 PP1 gene-encoding isoforms had no effect on phosphorylation of phospholamban, nor were Ca 2 + handling dynamics altered in adult myocytes from Ppp1cb deleted hearts. However, the loss of Ppp1cb from the heart, but not Ppp1ca or Ppp1cc, resulted in elevated phosphorylation of myofilament proteins such as myosin light chain 2 and cardiac myosin binding protein C, consistent with an enriched localization profile of this isoform to the sarcomeres. These results suggest a unique functional role for the PP1β isoform in affecting cardiac contractile function. Highlights: Deletion of PP1β protein from the heart results in concentric remodeling Deletion of PP1β protein from the heart leads to contractile dysfunction PP1β is targeted to the myofilaments over other PP1 isoforms Loss of PP1β increases phosphorylation of select myofilament proteins Individual deletion of PP1α, PP1β or PP1γ does not alter PLN phosphorylation