Is the failing heart out of fuel or a worn engine running rich? A study of mitochondria in old spontaneously hypertensive rats

Jüllig, Mia; Hickey, Anthony J. R.; Chai, Chau C.; Skea, Gretchen L.; Middleditch, Martin; Costa, Silvana; Choong, Soon Y.; Philips, Anthony; Cooper, Garth J. S.

doi:10.1002/pmic.200700977

Cited by 80 publications

(62 citation statements)

References 56 publications

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“…A previous study found that the 3-hydroxyacylcarnitines were absent in LCAD -/-tissues and a profound deficiency of acetylcarnitine was observed in LCAD -/-hearts, indicating that the cardiomyopathy in the LCAD -/-mouse is caused primarily by a severe energy deficiency in the heart, stressing the important role of LCAD in cardiac fatty acid metabolism in the mouse (27). LCAD was elevated in SHR cardiac mitochondria (121%) (28).…”

Section: Discussionmentioning

confidence: 94%

Aortic wall proteomic analysis in spontaneously hypertensive rats with a blood pressure decrease induced by 6-week load-free swimming

Hong

Li²,

Zhang

et al. 2015

Biomedical Reports

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Abstract. Decreased arterial compliance is one of the earliest detectable manifestations of adverse structural and functional changes within the vessel wall in hypertension. The proteomic approach is a powerful technique to analyze a complex mixture of proteins in various settings. Physical activity level was negatively associated with blood pressure. Sixteen 4-week-old male spontaneously hypertensive rats (SHR) and 16 Wistar-Kyoto (WKY) rats were randomly divided into four groups: i) SHR exercise group, ii) SHR rest group, iii) WKY exercise group and iv) WKY rest group. In the SHR and WKY exercise groups, rats were treated with a 6-week load-free swimming protocol (1 h/day, 5 days/week). The blood pressure of the rats was tested by the CODA TM2 single non-invasive blood pressure measurement appliance. After the 6-week swimming protocol, the total aorta excluding abdominal aorta was extracted. The proteins were separated by two-dimensional gel electrophoresis and identified via LC-mass spectrometry (MS)/MS. After 6-week load-free swimming, blood pressure decreased in the SHRs. Compared with sedentary SHRs, 11 spots on the 2D-gel showed a significant difference in exercised SHRs. Nine of these were chosen for further identification. There were 5 upregulated proteins (long-chain specific acyl-CoA dehydrogenase, heat shock protein β-1, isocitrate dehydrogenase subunit α, actin, α cardiac muscle 1 preprotein and calmodulin isoform 2) and 4 downregulated proteins (adipocyte-type fatty acid-binding protein, tubulin β-2C chain, 78 kDa glucose-regulated protein precursor and mimecan). Proteomics is an effective method to identify the target proteins of exercise intervention for hypertension. IntroductionHypertension is the most frequent chronic disease in the developed world. It is a multisystemic disease that affects the heart and kidneys among other organs. The overall functional, structural and biochemical alterations in vasculature have been extensively studied during hypertension, but the molecular mechanisms remain unclear. Decreased arterial compliance is one of the earliest detectable manifestations of adverse structural and functional changes within the vessel wall (1). It has been shown that the proteomic approach is a useful technique to analyze a complex mixture of proteins in various settings, usually by combining two-dimensional electrophoresis and mass spectrometry (MS) (2). Bian et al (3) recently analyzed the proteome of aorta from spontaneously hypertensive rats (SHR). They found that SHR showed a significant alteration in the aortic wall protein profile compared with normal rats.Exercise is a key antihypertensive therapy. It is reported that the physical activity level was negatively associated with blood pressure. In addition, the blood pressure can be decreased with long-term physical activity. Blood pressure of SHRs undergoing the physical activity protocol was lower than that of the normal SHRs. The functional and structural alterations in vasculature occurred in hypertensives following exercise t...

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Section: Discussionmentioning

confidence: 94%

Aortic wall proteomic analysis in spontaneously hypertensive rats with a blood pressure decrease induced by 6-week load-free swimming

Hong

Li²,

Zhang

et al. 2015

Biomedical Reports

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“…Indeed, a diminished ratio of PCr to ATP has been shown to be an excellent prognostic indicator of survival in human heart failure (112,113). Gene expression and proteomic profiling, together with ultrastructural studies, indicate that the expression of genes and proteins involved in mitochondrial energy transduction and respiration is downregulated in the late-stage failing heart (114)(115)(116)(117). In addition, several recent studies have revealed changes in the metabolome indicative of alterations (bottlenecks) in fuel oxidation and mitochondrial respiration (87,89,117).…”

Section: Energy Metabolic Derangements In the Failing Heartmentioning

confidence: 99%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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“…Mitochondrial protein content was determined using a BCA protein assay (Thermo Fisher Scientifi c, San Jose, CA). High-resolution respirometry was performed using 50 µg of mitochondrial protein per 2 ml chamber with the substrate and inhibitor addition protocol previously described ( 27,31 ).…”

Section: Multidimensional Mass Spectrometry-based Shotgun Lipidomic Amentioning

confidence: 99%

Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome

Kiebish

Yang

Liu

et al. 2013

Journal of Lipid Research

105

116

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Is the failing heart out of fuel or a worn engine running rich? A study of mitochondria in old spontaneously hypertensive rats

Cited by 80 publications

References 56 publications

Aortic wall proteomic analysis in spontaneously hypertensive rats with a blood pressure decrease induced by 6-week load-free swimming

Aortic wall proteomic analysis in spontaneously hypertensive rats with a blood pressure decrease induced by 6-week load-free swimming

Cardiac nuclear receptors: architects of mitochondrial structure and function

Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome

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