O‐GlcNAc Transferase Promotes Compensated Cardiac Function and Protein Kinase A O‐GlcNAcylation During Early and Established Pathological Hypertrophy From Pressure Overload

Autor: Danny El-Nachef, Wei Zhong Zhu, Xiulan Yang, Aaron K Olson, Dolena R Ledee
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Glycosylation
Time Factors
030204 cardiovascular system & hematology
Ventricular Function
Left
Muscle hypertrophy
O glcnacylation
Ventricular Dysfunction
Left
0302 clinical medicine
Phosphorylation
Original Research
Mice
Knockout
Ventricular Remodeling
cardiac hypertrophy
Remodeling
Cardiac hypertrophy
cardiovascular system
Hypertrophy
Left Ventricular
Cardiology and Cardiovascular Medicine
Cardiac function curve
medicine.medical_specialty
O-GlcNAc transferase
N-Acetylglucosaminyltransferases
protein kinase A phosphorylation
Sarcoplasmic Reticulum Calcium-Transporting ATPases
03 medical and health sciences
Internal medicine
medicine
Animals
Calcium Signaling
Protein kinase A
Pathological
Pressure overload
Heart Failure
business.industry
Myocardium
Calcium-Binding Proteins
Troponin I
pressure overload
Cyclic AMP-Dependent Protein Kinases
Disease Models
Animal
030104 developmental biology
Endocrinology
Animal Models of Human Disease
cardiac failure
OGT
business
O‐GlcNAc
Basic Science Research
Cell Signalling/Signal Transduction
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: Background Protein posttranslational modifications by O ‐linked β‐N‐acetylglucosamine (O‐GlcNAc) increase with cardiac hypertrophy, yet the functional effects of these changes are incompletely understood. In other organs, O‐GlcNAc promotes adaptation to acute physiological stressors; however, prolonged O‐GlcNAc elevations are believed to be detrimental. We hypothesize that early O‐GlcNAcylation improves cardiac function during initial response to pressure overload hypertrophy, but that sustained elevations during established pathological hypertrophy negatively impact cardiac function by adversely affecting calcium handling proteins. Methods and Results Transverse aortic constriction or sham surgeries were performed on littermate controls or cardiac‐specific, inducible O‐GlcNAc transferase knockout (OGTKO) mice to reduce O‐GlcNAc levels. O‐GlcNAc transferase deficiency was induced at different times. To evaluate the initial response to pressure overload, OGTKO was completed preoperatively and mice were followed for 2 weeks post‐surgery. To assess prolonged O‐GlcNAcylation during established hypertrophy, OGTKO was performed starting 18 days after surgery and mice were followed until 6 weeks post‐surgery. In both groups, OGTKO with transverse aortic constriction caused significant left ventricular dysfunction. OGTKO did not affect levels of the calcium handling protein SERCA2a. OGTKO reduced phosphorylation of phospholamban and cardiac troponin I, which would negatively impact cardiac function. O‐GlcNAcylation of protein kinase A catalytic subunit, a kinase for phospholamban, decreased with OGTKO. Conclusions O‐GlcNAcylation promotes compensated cardiac function in both early and established pathological hypertrophy. We identified a novel O‐GlcNAcylation of protein kinase A catalytic subunit, which may regulate calcium handling and cardiac function.
Databáze: OpenAIRE
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