Selective inhibition of OCTN2 is more effective than inhibition of gamma-butyrobetaine dioxygenase to decrease the availability of l-carnitine and to reduce myocardial infarct size.
l-Carnitine is a cofactor in the energy metabolism pathways where it drives the uptake and oxidation of long chain fatty acids (LCFA) by mitochondria. LCFA lipotoxicity causes mitochondrial damage and results in an insufficient energy supply and a decrease in l-carnitine content limits LCFA flux and protects mitochondria. Here, we tested whether the inhibition of GBB dioxygenase (BBOX) or organic cation transporter 2 (OCTN2) is the most effective strategy to decrease l-carnitine content. The activity of 51 compounds was tested and we identified selective inhibitors of OCTN2. In contrast to selective inhibitors of BBOX, OCTN2 inhibitors induced a 10-fold decrease in l-carnitine content in the heart tissues and a significant 35% reduction of myocardial infarct size. In addition, OCTN2 inhibition correlated with the inhibitor content in the heart tissues, and OCTN2 could potentially be an efficient target to increase drug transport into tissues and to reduce drug elimination by urine. In conclusion, the results of this study confirm that selective inhibition of OCTN2, compared to selective inhibition of BBOX, is a far more effective approach to decrease l-carnitine content and to induce cardioprotective effects. OCTN2 could potentially be an efficient tool to increase drug transport in tissues and to reduce drug elimination via urine.
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia. Electronic address: ledgars@biomed.lu.lv.
Edgars
E
Liepinsh
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga LV1007, Latvia.
Marina
M
Makrecka
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia.
Janis
J
Kuka
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia.
Helena
H
Cirule
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia.
Elina
E
Makarova
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia.
Eduards
E
Sevostjanovs
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia.
Solveiga
S
Grinberga
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga LV1007, Latvia.
Reinis
R
Vilskersts
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia.
Daina
D
Lola
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia.
Einars
E
Loza
JSC Grindex, Krustpils Str. 53, Riga LV-1057, Latvia.
Ilmars
I
Stonans
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia.
Osvalds
O
Pugovics
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga LV1007, Latvia.
Maija
M
Dambrova
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002331:Carnitine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D017208:Rats, Wistar; D000074058:Solute Carrier Family 22 Member 5; D050563:gamma-Butyrobetaine Dioxygenase / Q000037:antagonists & inhibitors*
D002316:Cardiotonic Agents; D027701:Organic Cation Transport Proteins; C115441:Slc22a5 protein, rat; D000074058:Solute Carrier Family 22 Member 5; D050563:gamma-Butyrobetaine Dioxygenase; D002331:Carnitine
Biosynthesis; Cardioprotection; Drug delivery; Reabsorbtion in kidneys; Transport