Kuka 2018 MiP2018
Long-chain acylcarnitines (LCAC) are intermediates of fatty acids that ensure long-chain fatty acid transport into mitochondria. Increased availability of LCAC is associated with the severity of cardiometabolic disorders like ischemia-reperfusion (IR) damage and the development of insulin resistance. We hypothesized that compounds that decrease carnitine availability by inhibiting GBB dioxygenase (BBOX) and organic cation transporter 2 (OCTN2) could decrease LCAC content and may represent an effective treatment for cardiometabolic diseases.
The cardioprotective effects of an inhibitor of OCTN2 and BBOX, methyl-GBB (4-[ethyl(dimethyl)ammonio] butanoate), was studied in Wistar rat heart ex vivo (Langendorff) and in vivo infarction models. Effects of acute addition of carnitine on LCAC cardiac content and anti-infarction effect were evaluated in methyl-GBB treated rat ex vivo heart infarction model. LCAC content changes in the heart and duration of anti-infarction effect post-treatment (28 days) were evaluated. High-resolution fluoro-respirometry was used to evaluate mitochondrial damage after IR and efficacy of therapy. The cardioprotective properties of methyl-GBB were evaluated also in an experimental model of atherosclerosis using apoE-/- mice.
Selective inhibition of OCTN2, compared to selective inhibition of BBOX, was found to be a far more effective approach to decrease carnitine content. The treatment with methyl-GBB significantly decreased LCAC content in plasma, cardiac and muscle tissues. Methyl-GBB long-term treatment decreased fatty acid oxidation, increased glucose oxidation in the heart and decreased the infarct size by 45-48% ex vivo and in vivo. The addition of 2 mM carnitine to isolated heart perfusate significantly diminished the methyl-GBB-induced decrease in LCAC content and increased infarct size. The anti-infarction effect of methyl-GBB lasted for at least 2 weeks post-treatment and at least 70% decrease in LCAC content was required to protect ischemic heart tissues. Methyl-GBB treatment protected against the mitochondrial dysfunction induced by IR. Mitochondria respiration rate at OXPHOS state was increased by 50% compared with ischemic control and, for LEAKT respiration, methyl-GBB completely protected against IR-induced mitochondrial uncoupling. In apoE−/− mice, methyl-GBB treatment decreased LCAC content in aortic tissues seventeen-fold and the size of atherosclerotic plaques by 36%.
Selective inhibition of OCTN2 is the most effective approach to decrease carnitine and LCAC contents. Decrease in LCAC content and following changes in metabolism pattern are responsible for the cardioprotective effects of methyl-GBB. Altogether targeting LCAC availability provides a new therapeutic approach against cardiometabolic diseases.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cardiovascular Stress:Ischemia-reperfusion Organism: Rat Tissue;cell: Heart
Coupling state: LEAK, OXPHOS
- Latvian Inst Organic Synthesis, Riga, Latvia. - [email protected]