New target for cardioprotective therapies

A novel target for cardioprotective therapies – enzyme N6-trimethyllysine dioxygenase (TMLD) – has been identified by researchers from the Latvian Institute of Organic Synthesis (LIOS), the Tartu University (TU) and Riga Stradins University (RSU). This research is published in the journal “Free Radical Biology and Medicine” (IF= 7.376).

TMLD is the first enzyme in the carnitine/acylcarnitine biosynthesis pathway. It has been already known that increased tissue content of long-chain acylcarnitines may induce mitochondrial and cardiac damage. Despite extensive studies of cardiac fatty acid metabolism, the genetic inactivation of enzymes in the carnitine synthesis pathway to prevent long-chain acylcarnitine accumulation and prove its role has never been tested so far.

A constitutive whole body TMLHE mutant mice model which is characterized by a lower carnitine and acylcarnitine content in heart tissues has been developed for the first time by researchers at LIOS, TU and RSU. They demonstrated that a TMLD enzyme deficiency and accordingly the lower level of carnitine did not cause any severe phenotype, heart and muscle functions in mutant animals were completely normal.

Using this mice model, researchers provided experimental evidence that the decrease of long-chain acylcarnitines in the heart ensures the cardiometabolic changes that lead to mitochondrial survival and reduced infarct size during ischemia-reperfusion.

These studies also have demonstrated that the arrest of the carnitine synthesis pathway primary affects polyunsaturated fatty acid metabolism and elevates their plasma levels and abundance in the whole lipidome. This opens new avenues in the polyunsaturated fatty acid supplementation field.

This research was supported by the Latvian Council of Science, project TRILYSOX, grant No. LZP-2018/1-0082 and authors were supported by the European Union’s Horizon 2020 research and innovation programme, project Fat4Brain, grant agreement No 857394.

Read the article:

Liepinsh, E.; Kuka, J.; Vilks, K.; Svalbe, B.; Stelfa, G.; Vilskersts, R.; Sevostjanovs, E.; Goldins, N. R.; Groma, V.; Grinberga, S.; Plaas, M.; Makrecka-Kuka, M.; Dambrova, M.

Low cardiac content of long-chain acylcarnitines in TMLHE knockout mice prevents ischaemia-reperfusion-induced mitochondrial and cardiac damage.

Free Radic. Biol. Med. 2021, 177, 370-380. DOI: 10.1016/j.freeradbiomed.2021.10.035