title: Selective regulation of cardiac organic cation transporter novel type 2 (OCTN2) in dilated cardiomyopathy.
abstract: Organic cation transporters (OCT1-3 and OCTN1/2) facilitate cardiac uptake of endogenous compounds and numerous drugs. Genetic variants of OCTN2, for example, reduce uptake of carnitine, leading to heart failure. Whether expression and function of OCTs and OCTNs are altered by disease has not been explored in detail. We therefore studied cardiac expression, heart failure-dependent regulation, and affinity to cardiovascular drugs of these transporters. Cardiac transporter mRNA levels were OCTN2>OCT3>OCTN1>OCT1 (OCT2 was not detected). Proteins were localized in vascular structures (OCT3/OCTN2/OCTN1) and cardiomyocytes (OCT1/OCTN1). Functional studies revealed a specific drug-interaction profile with pronounced inhibition of OCT1 function, for example, carvedilol [half maximal inhibitory concentration (IC₅₀), 1.4 μmol/L], diltiazem (IC₅₀, 1.7 μmol/L), or propafenone (IC₅₀, 1.0 μmol/L). With use of the cardiomyopathy model of coxsackievirus-infected mice, Octn2mRNA expression was significantly reduced (56% of controls, 8 days after infection). Accordingly, in endomyocardial biopsy specimens OCTN2 expression was significantly reduced in patients with dilated cardiomyopathy, whereas the expression of OCT1-3 and OCTN1 was not affected. For OCTN2 we observed a significant correlation between expression and left ventricular ejection fraction (r = 0.53, P < 0.0001) and the presence of cardiac CD3⁺ T cells (r = -0.45, P < 0.05), respectively. OCT1, OCT3, OCTN1, and OCTN2 are expressed in the human heart and interact with cardiovascular drugs. OCTN2 expression is selectively reduced in dilated cardiomyopathy patients and predicts the impairment of cardiac function.
authors.affiliation: Department of Pharmacology, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Sabine
authors.initials: S
authors.lastname: Ameling
authors.forename: Michel
authors.initials: M
authors.lastname: Noutsias
authors.forename: Kathleen
authors.initials: K
authors.lastname: Köck
authors.forename: Ivonne
authors.initials: I
authors.lastname: Triebel
authors.forename: Karina
authors.initials: K
authors.lastname: Bonitz
authors.forename: Konrad
authors.initials: K
authors.lastname: Meissner
authors.forename: Gabriele
authors.initials: G
authors.lastname: Jedlitschky
authors.forename: Lars R
authors.initials: LR
authors.lastname: Herda
authors.forename: Markus
authors.initials: M
authors.lastname: Reinthaler
authors.forename: Maria
authors.initials: M
authors.lastname: Rohde
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hoffmann
authors.forename: Uwe
authors.initials: U
authors.lastname: Kühl
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kandolf
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001706:Biopsy; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D002317:Cardiovascular Agents / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D002317:Cardiovascular Agents; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger