Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet‐Induced Metabolic Heart Disease

Abstract

BackgroundMitochondrial reactive oxygen species (ROS) are associated with metabolic heart disease (MHD). However, the mechanism by which ROS cause MHD is unknown. We tested the hypothesis that mitochondrial ROS are a key mediator of MHD.Methods and ResultsMice fed a high‐fat high‐sucrose (HFHS) diet develop MHD with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild‐type mice were fed an HFHS or control diet for 4 months. Cardiac mitochondria from HFHS‐fed wild‐type mice had a 3‐fold greater rate of H2O2 production (P=0.001 versus control diet fed), a 30% decrease in complex II substrate–driven oxygen consumption (P=0.006), 21% to 23% decreases in complex I and II substrate–driven ATP synthesis (P=0.01), and a 62% decrease in complex II activity (P=0.002). In transgenic mice that express catalase in mitochondria, all HFHS diet–induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In HFHS‐fed wild‐type mice complex II substrate–driven ATP synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site‐directed mutation of complex II subunit B Cys100 or Cys103 to redox‐insensitive serines prevented complex II dysfunction induced by ROS or high glucose/high palmitate in the medium.ConclusionMitochondrial ROS are pathogenic in MHD and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and II proteins including reversible oxidative posttranslational modifications of complex II subunit B Cys100 and Cys103.

Decreased ATP production and myocardial contractile reserve in metabolic heart disease

“…1D). Thus, under basal conditions HFHS feeding led to diastolic dysfunction with preservation of systolic function confirming our prior echocardiographic findings [10,11] and showing that this isolated heart preparation exhibits hemodynamic features consistent with MHD.…”

“…This was evident even at low LV volumes well within the physiologic range of LVEDP of 0–35 mm Hg. We previously showed that HFHS feeding for 4 months led to diastolic dysfunction in mice in vivo as reflected by abnormal LV filling and slowed LV relaxation measured by Doppler echocardiography [10]. The current ex vivo finding of impaired diastolic function in the isolated beating heart is consistent with our prior in vivo echocardiographic findings, showing that the diastolic dysfunction we observed in the isolated beating heart is of physiologic relevance.…”

“…This thesis is further supported by observations in genetic or diet-induced models of MHD showing an impaired metabolic efficiency in working hearts [9]. Likewise, we [10,11] and others [12,13] have shown that maximal ATP production is decreased in isolated cardiac mitochondria from mice or rats with diet-induced MHD. However, there are at least two important limitations to our current understanding of energetics in MHD.…”

“…The daily caloric intake was approximately 11% higher in HFHS group (Table 1). We previously showed that 4 months of HFHS diet leads to LV hypertrophy and diastolic dysfunction as assessed by trans-mitral and tissue Doppler echocardiography [10,11]. HFHS-fed mice recapitulate many aspects of the metabolic syndrome, including insulin resistance, increased plasma triglycerides and hypertension, making them an excellent model to study obesity-linked cardiovascular complications [18].…”

“…MHD was caused by feeding mice a high fat, high sucrose, (HFHS) “Western” diet for 4 months [10,14]. Myocardial function was measured in the isolated perfused beating heart, and myocardial energetics were assessed using 31 P NMR spectroscopy [15-17].…”