Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations
| العنوان: | Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations |
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| المؤلفون: | George G. Schweitzer, Carla J. Weinheimer, Rita T. Brookheart, Kari T. Chambers, Alison R. Swearingen, Kyle S. McCommis, Timothy R. Koves, Michael A. Cooper, Attila Kovacs, Brian N. Finck, Deborah M. Muoio |
| المصدر: | JCI Insight JCI Insight, Vol 6, Iss 9 (2021) |
| بيانات النشر: | American Society for Clinical Investigation, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cardiac function curve, medicine.medical_specialty, Cardiotonic Agents, Cardiolipins, Cardiology, Phosphatidate Phosphatase, Succinic Acid, Phosphatidic Acids, Cardiomegaly, Mitochondrion, Mitochondria, Heart, Diglycerides, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Internal medicine, Dobutamine, Pyruvic Acid, Cardiolipin, medicine, Animals, Protein kinase A signaling, Triglycerides, Diacylglycerol kinase, Pressure overload, Mice, Knockout, Exercise Tolerance, Chemistry, Myocardium, General Medicine, Cardiovascular disease, Cyclic AMP-Dependent Protein Kinases, Myocardial Contraction, Mitochondria, Disease Models, Animal, 030104 developmental biology, Endocrinology, Metabolism, 030220 oncology & carcinogenesis, Intermediary metabolism, cardiovascular system, Medicine, Homeostasis, Ionotropic effect, Research Article |
| الوصف: | Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1-/- hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1-/- mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling. |
| اللغة: | English |
| تدمد: | 2379-3708 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ee4375e3db62d28d3deb3147af74419a http://europepmc.org/articles/PMC8262319 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ee4375e3db62d28d3deb3147af74419a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23793708 |
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