title: Reduced sarcolemmal expression and function of the NBCe1 isoform of the Na⁺-HCO₃⁻ cotransporter in hypertrophied cardiomyocytes of spontaneously hypertensive rats: role of the renin-angiotensin system.
abstract: OBJECTIVE
  Electroneutral (NBCn1) and electrogenic (NBCe1) isoforms of the Na(+)-HCO3(-) cotransporter (NBC) coexist in the heart. We studied the expression and function of these isoforms in hearts of Wistar and spontaneously hypertensive rats (SHR), elucidating the direct implication of the renin-angiotensin system in the NBC regulation.
  
  
  RESULTS
  We used myocytes from Wistar, SHR, losartan-treated SHR (Los-SHR), and Angiotensin II (Ang II)-induced cardiac hypertrophy. We found an overexpression of NBCe1 and NBCn1 proteins in SHR that was prevented in Los-SHR. Hyperkalaemic-induced pHi alkalization was used to study selective activation of NBCe1. Despite the increase in NBCe1 expression, its activity was lower in SHR than in Wistar or Los-SHR. Similar results were found in Ang II-induced hypertrophy. A specific inhibitory antibody against NBCe1 allowed the discrimination between NBCe1 and NBCn1 activity. Whereas in SHR most of the pHi recovery was due to NBCn1 stimulation, in Wistar and Los-SHR the activity of both isoforms was equitable, suggesting that the deteriorated cardiac NBCe1 function observed in SHR is compensated by an enhanced activity of NBCn1. Using the biotin method, we observed greater level of internalized NBCe1 protein in SHR than in the non-hypertophic groups, while with immunofluorescence we localized the protein in endosomes near the nucleus only in SHR.
  
  
  CONCLUSIONS
  We conclude that Ang II is responsible for the impairment of the NBCe1 in hypertrophied hearts. This is due to retained transporter protein units in early endosomes. Moreover, NBCn1 activity seems to be increased in the hypertrophic myocardium of SHR, compensating impaired function of NBCe1.
authors.affiliation: Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata-CONICET, Calle 60 y 120, 1900 La Plata, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Orlowski
authors.forename: María C
authors.initials: MC
authors.lastname: Ciancio
authors.forename: Claudia I
authors.initials: CI
authors.lastname: Caldiz
authors.forename: Verónica C
authors.initials: VC
authors.lastname: De Giusti
authors.forename: Ernesto A
authors.initials: EA
authors.lastname: Aiello
mesh_terms: D064751:Ammonium Compounds / Q000378:metabolism; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006947:Hyperkalemia / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011188:Potassium / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects; D012508:Sarcolemma / Q000378:metabolism* / Q000473:pathology; D027982:Sodium-Bicarbonate Symporters / Q000378:metabolism*; D013997:Time Factors
chemical_list: D064751:Ammonium Compounds; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001639:Bicarbonates; C422004:Slc4a4 protein, rat; C498902:Slc4a7 protein, rat; D027982:Sodium-Bicarbonate Symporters; D000804:Angiotensin II; D019808:Losartan; D011188:Potassium
keywords: Cardiac hypertrophy; Cardiac myocytes; Na+–HCO3- cotransporter