title: A novel endothelin receptor antagonist CPU0213 improves diabetic cardiac insufficiency attributed to up-regulation of the expression of FKBP12.6, SERCA2a, and PLB in rats.
abstract: The depressed sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) and Ca2+-release channels (ryanodine receptor RyR2) are involved in the diabetic cardiomyopathy. However, an implication of a down-regulation of FK506-binding protein or calstabin-2 (FKBP12.6) is undefined. It was hypothesized that the down-regulation of FKBP12.6 and SERCA2a of the intracellular calcium handling system is closely related to an up-regulated endothelin (ET) system. An ET receptor antagonist CPU0213 is newly discovered and expected to ameliorate cardiac insufficiency which is mediated by the depressed FKBP12.6 and SERCA2a in diabetic rat heart. Diabetes was developed in male Sprague-Dawley rats 8 weeks after an injection of streptozotocin (60 mg/kg IP), and CPU0213 was instituted 30 mg/kg, SC in the last 4 weeks. The assessment of the cardiac function, cardiac calcium handling proteins, endothelin system, and redox enzyme system were conducted. The compromised cardiac function in diabetic rats was accompanied by a significant down-regulation of expression of FKBP12.6 as well as SERCA2a and phospholamban. These were closely linked with an increased ET-1 and up-regulation of endothelin converting enzyme, PropreET1, and inducible nitric oxide synthase mRNA in diabetic cardiomyopathy. After 4-week treatment, CPU0213 was capable to attenuate completely the down-regulated FKBP12.6 and SERCA2a, and up-regulated ET system in association with a recovery of the cardiac insufficiency of diabetic cardiomyopathy.
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Min-You
authors.initials: MY
authors.lastname: Qi
authors.forename: Hui-jing
authors.initials: HJ
authors.lastname: Xia
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis; D001794:Blood Pressure; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000096:biosynthesis*; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D048909:Diabetes Complications / Q000188:drug therapy* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental; D015536:Down-Regulation; D065128:Endothelin Receptor Antagonists; D000072396:Endothelin-Converting Enzymes; D006339:Heart Rate; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009929:Organ Size; D018384:Oxidative Stress; D011720:Pyrazoles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis*; D013311:Streptozocin; D022061:Tacrolimus Binding Protein 1A / Q000096:biosynthesis*; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*; D000099211:Phospholamban
chemical_list: D016282:Aspartic Acid Endopeptidases; D002135:Calcium-Binding Proteins; D065128:Endothelin Receptor Antagonists; D000072396:Endothelin-Converting Enzymes; D008666:Metalloendopeptidases; D052247:Nitric Oxide Synthase Type II; D011720:Pyrazoles; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013311:Streptozocin; D022061:Tacrolimus Binding Protein 1A; D014662:Vasoconstrictor Agents; D000099211:Phospholamban; C506948:Atp2a2 protein, rat; C513821:CPU0213