title: Liguzinediol Enhances the Inotropic Effect of Rat Hearts via Inhibition of Protein Phosphatase (PP1 and PP2A) Activities.
abstract: It has been demonstrated that liguzinediol (2,5-dihydroxymethyl-3,6-dimethylpyrazine, LZDO), a derivative of ligustrazine from Ligusticum wallichii Franch, exerts positive inotropy in isolated rat heart mediated by the sarcoplasmic reticulum Ca-ATPase (SERCA2a). Here, we further explore the underlying mechanism of the positive inotropic effect of LZDO in rat hearts. In vivo and ex vivo rat heart experiments, biochemistry, and Western blot techniques were used to analyze the rat heart contractility, and SERCA2a activity, phospholamban (PLB) phosphorylation, and protein phosphatase (PP1 and PP2A) activities in rat left ventricular myocytes, respectively. LZDO (20 mg/kg) significantly increased the inotropy of rat heart in vivo. In isolated rat heart experiments, LZDO (100 μM) restored the decreased inotropy induced by caffeine (0.5 mM); however, calyculin A (4 nM), an inhibitor of PP1 and PP2A, eliminated the inotropic effect of LZDO (100 μM). Moreover, LZDO (1, 10, and 100 μM) significantly enhanced SERCA2a activity and increased the levels of phosphorylated PLB on both serine-16 (Ser-16) and threonine-17 (Thr-17). In addition, LZDO (100 μM) significantly inhibited the activities of PP1 and PP2A. The positive inotropic effects of LZDO on in vivo and ex vivo rat hearts seem to be mediated through inhibition of PP1/PP2A, which may suppress dephosphorylated PLB and enhance SERCA2a activity. LZDO may prove effective in treating heart failure in clinical settings based on its unique biological mechanism.
authors.affiliation: *National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China; †Department of Respiratory, Inpatient Wards for Senior Cadres, Nanjing General Hospital of Nanjing Military Command Region, Nanjing, China; ‡First Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, China; and §Institute of Chinese Medicine of Taizhou China Medical City, Taizhou, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.forename: Huili
authors.initials: H
authors.lastname: Huang
authors.forename: Mengdan
authors.initials: M
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Shuyin
authors.initials: S
authors.lastname: Xue
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.forename: Ming
authors.initials: M
authors.lastname: Xie
authors.forename: Kesu
authors.initials: K
authors.lastname: Chen
authors.forename: Fuming
authors.initials: F
authors.lastname: Liu
authors.forename: Long
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008387:Marine Toxins; D009924:Organ Culture Techniques; D010080:Oxazoles / Q000494:pharmacology; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: C572935:2,5-dihydroxymethyl-3,6-dimethylpyrazine; D002120:Calcium Channel Agonists; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D011719:Pyrazines; C059041:calyculin A; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases