Hypertension-linked decrease in the expression of brain gamma-adducin.
Gene profiling data coupled with adducin polymorphism studies led us to hypothesize that decreased expression of this cytosolic protein in the brain could be a key event in the central control of hypertension. Thus, our objectives in the present study were to (1) determine which adducin subunit gene demonstrates altered expression in the hypothalamus and brainstem (two cardioregulatory-relevant brain areas) in two genetic strains of hypertensive rats and (2) analyze the role of adducins in neurotransmission at the cellular level. All three adducin subunits (alpha, beta, and gamma) were present in the hypothalamus and brainstem of Wistar Kyoto (WKY) and spontaneously hypertensive (SH) rats. However, only the gamma-adducin subunit expression was 40% to 60% lower in the SH rat compared with WKY rat. A similar decrease in gamma-adducin expression was observed in the hypothalamus and brainstem of the renin transgenic rat compared with its normotensive control. Losartan treatment of the SH rat failed to normalize gamma-adducin gene expression. A hypertension-linked decrease of gamma-adducin was confirmed by demonstrating a decrease in gamma-adducin expression in hypothalamic/brainstem neuronal cultures from prehypertensive SH rats. Neuronal firing rate was evaluated to analyze the role of this protein in neurotransmission. Perfusion of a gamma-adducin-specific antibody caused a 2-fold increase in the neuronal firing rate, an effect similar to that observed with angiotensin II. Finally, we observed that preincubation of neuronal cultures for 8 hours with 100 nmol/L angiotensin II caused a 60% decrease in endogenous gamma-adducin and was associated with a 2-fold increase in basal firing rate. These observations support our hypothesis that a decrease in gamma-adducin expression in cardioregulatory-relevant brain areas is linked to hypertension possibly by regulating the release of neurotransmitters.
D000200:Action Potentials; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D001933:Brain Stem / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D021122:Protein Subunits; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014158:Transcription, Genetic; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D000099291:Adducins