Cardiac Mitochondria Dysfunction in Dyslipidemic Mice

Abstract

Dyslipidemia triggers many severe pathologies, including atherosclerosis and chronic inflammation. Several lines of evidence, including our studies, have suggested direct effects of dyslipidemia on cardiac energy metabolism, but details of these effects are not clear. This study aimed to investigate how mild dyslipidemia affects cardiac mitochondria function and vascular nucleotide metabolism. The analyses were performed in 3- and 6-month-old knock-out mice for low-density lipoprotein receptor (Ldlr−/−) and compared to wild-type C57Bl/6J mice (WT). Cardiac isolated mitochondria function was analyzed using Seahorse metabolic flux analyzer. The mechanical function of the heart was measured using echocardiography. The levels of fusion, fission, and mitochondrial biogenesis proteins were determined by ELISA kits, while the cardiac intracellular nucleotide concentration and vascular pattern of nucleotide metabolism ecto-enzymes were analyzed using reverse-phase high-performance liquid chromatography. We revealed the downregulation of mitochondrial complex I, together with a decreased activity of citrate synthase (CS), reduced levels of nuclear respiratory factor 1 and mitochondrial fission 1 protein, as well as lower intracellular adenosine and guanosine triphosphates’ pool in the hearts of 6-month Ldlr−/− mice vs. age-matched WT. The analysis of vascular ecto-enzyme pattern revealed decreased rate of extracellular adenosine monophosphate hydrolysis and increased ecto-adenosine deaminase activity (eADA) in 6-month Ldlr−/− vs. WT mice. No changes were observed in echocardiography parameters in both age groups of Ldlr−/− mice. Younger hyperlipidemic mice revealed no differences in cardiac mitochondria function, CS activity, intracellular nucleotides, mitochondrial biogenesis, and dynamics but exhibited minor changes in vascular eADA activity vs. WT. This study revealed that dysfunction of cardiac mitochondria develops during prolonged mild hyperlipidemia at the time point corresponding to the formation of early vascular alterations.

Mitochondria-targeting EGCG derivatives protect H9c2 cardiomyocytes from H2O2-induced apoptosis: design, synthesis and biological evaluation

“…34 Mitochondrial function is highly regulated by the mitochondrial outer membrane potential ( Ψ m ) and it plays an important role in mitochondrial biogenesis and metabolism. 35–37 Pretreatment of MitoEGCG 4 and MitoEGCG 6 attenuated the loss of Ψ m induced by H 2 O 2 treatment in H9c2 cells in comparison to EGCG. It was also observed that EGCG was reducing the Ψ m of cells at concentrations above 50 μM and therefore acting as a pro-oxidant to cardiomyocyte cells (Fig.…”

Hidden Pool of Cardiac Adenine Nucleotides That Controls Adenosine Production

“…The electron flow assay was performed as described previously [54]. Briefly, isolated mitochondria from a rat's heart were suspended in a mitochondrial assay solution (MAS, 1×), which contained 70 mM sucrose, 220 mM mannitol, 10 mM KH 2 PO 4 , 1 mM ethylene glycol-bis(β-aminoethyl ether)-N,N,N ,N -tetraacetic acid tetrasodium salt (EGTA), 5 mM MgCl 2 , 2 mM 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid sodium salt, N-(2-Hydroxyethyl)piperazine-N -(2-ethanesulfonic acid) sodium salt (HEPES), and 0.2 % (w/v) albumin bovine serum (BSA), pH 7.2.…”

Blocking cholesterol formation and turnover improves cellular and mitochondria function in murine heart microvascular endothelial cells and cardiomyocytes

“…Murine in vivo or cellular models are useful for studying atherosclerosis ethology, pathogenesis, and complications, providing a valuable platform for testing different pharmacological approaches ( Lee et al, 2017 ). Recently, we have documented an impairment in cardiac mitochondria function in mouse model of human-like dyslipidemia ( Braczko et al, 2022 ). The aim of this work was to investigate the pleiotropic effects of statins and PCSK9i on mitochondrial and cellular function of cardiac endothelial cells and cardiomyocytes.…”