title: Transgenic rescue of defective Cd36 enhances myocardial adenylyl cyclase signaling in spontaneously hypertensive rats.
abstract: Dysfunction or abnormalities in the regulation of fatty acid translocase Cd36, a multifunctional membrane protein participating in uptake of long-chain fatty acids, has been linked to the development of heart diseases both in animals and humans. We have previously shown that the Cd36 transgenic spontaneously hypertensive rat (SHR-Cd36), with a wild type Cd36, has higher susceptibility to ischemic ventricular arrhythmias when compared to spontaneously hypertensive rat (SHR) carrying a mutant Cd36 gene, which may have been related to increased β-adrenergic responsiveness of these animals (Neckar et al., 2012 Physiol. Genomics 44:173-182). The present study aimed to determine whether the insertion of the wild type Cd36 into SHR would affect the function of myocardial G protein-regulated adenylyl cyclase (AC) signaling. β-Adrenergic receptors (β-ARs) were characterized by radioligand-binding experiments and the expression of selected G protein subunits, AC, and protein kinase A (PKA) was determined by RT-PCR and Western blot analyses. There was no significant difference in the amount of trimeric G proteins, but the number of β-ARs was higher (by about 35 %) in myocardial preparations from SHR-Cd36 as compared to SHR. Besides that, transgenic rats expressed increased amount (by about 20 %) of the dominant myocardial isoforms AC5/6 and contained higher levels of both nonphosphorylated (by 11 %) and phosphorylated (by 45 %) PKA. Differently stimulated AC activity in SHR-Cd36 significantly exceeded (by about 18-30 %) the enzyme activity in SHR. Changes at the molecular level were reflected by higher contractile responses to stimulation by the adrenergic agonist dobutamine. In summary, it can be concluded that the increased susceptibility to ischemic arrhythmias of SHR-Cd36 is attributable to upregulation of some components of the β-AR signaling pathway, which leads to enhanced sensitization of AC and increased cardiac adrenergic responsiveness.
authors: Department of Cell Biology, Faculty of Science, Charles University in Prague, Vinicna 7, 128 44, Prague 2, Czech Republic.
authors: Martina
authors: M
authors: Klevstig
authors: Dmitry
authors: D
authors: Manakov
authors: Dita
authors: D
authors: Kasparova
authors: Iveta
authors: I
authors: Brabcova
authors: Frantisek
authors: F
authors: Papousek
authors: Jitka
authors: J
authors: Zurmanova
authors: Vaclav
authors: V
authors: Zidek
authors: Jan
authors: J
authors: Silhavy
authors: Jan
authors: J
authors: Neckar
authors: Michal
authors: M
authors: Pravenec
authors: Frantisek
authors: F
authors: Kolar
authors: Olga
authors: O
authors: Novakova
authors: Jiri
authors: J
authors: Novotny
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D055647:Rats, Transgenic; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D018955:CD36 Antigens; D011943:Receptors, Adrenergic, beta; D004280:Dobutamine; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases
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