Transgenic rescue of defective Cd36 enhances myocardial adenylyl cyclase signaling in spontaneously hypertensive rats

0398826 - FGÚ 2014 RIV US eng J - Článek v odborném periodiku
Klevstig, M. - Manakov, D. - Kašparová, D. - Brabcová, I. - Papoušek, František - Žurmanová, J. - Zídek, Václav - Šilhavý, Jan - Neckář, Jan - Pravenec, Michal - Kolář, František - Nováková, O. - Novotný, J.
Transgenic rescue of defective Cd36 enhances myocardial adenylyl cyclase signaling in spontaneously hypertensive rats.
Pflugers Archiv - European Journal of Physiology. Roč. 465, č. 10 (2013), s. 1477-1486. ISSN 0031-6768. E-ISSN 1432-2013
Grant CEP: GA MŠMT(CZ) LL1204; GA AV ČR(CZ) IAAX01110901; GA ČR(CZ) GAP303/10/0505
Institucionální podpora: RVO:67985823
Klíčová slova: SHR rats * Cd36 * heart * beta-Adrenergic receptors * Adenylyl cyclase * Protein kinase A
Kód oboru RIV: ED - Fyziologie
Impakt faktor: 3.073, rok: 2013

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 beta-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. beta-Adrenergic receptors (beta-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 andWestern blot analyses. There was no significant difference in the amount of trimeric G proteins, but the number of beta-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 SHRCd36 significantly exceeded (by about 18–30 %) the enzyme activity in SHR. Changes at themolecular 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 beta-AR signaling pathway, which leads to enhanced sensitization of AC and increased cardiac adrenergic responsiveness
Trvalý link: http://hdl.handle.net/11104/0226235