Alterations of Mitochondrial Enzymes Contribute to Cardiac Hypertrophy before Hypertension Development in Spontaneously Hypertensive Rats

Meng, Chao; Jin, Xian; Li, Xia; Shen, Shao‐Ming; Wang, Xiaoling; Cai, Jun; Chen, Guoqiang; Wang, Li‐Shun; Fang, Ningyuan

doi:10.1021/pr801059u

Cited by 44 publications

(47 citation statements)

References 75 publications

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“…Some studies identified bidirectional changes in the ETC subunit composition. [29][30][31][32][33] However, a study using the same mouse model as our experiments reported that ETC protein levels were mostly increased in heart failure, 32 which is consistent with our results. In the present study, carbonylation, tyrosine nitration, and cysteine oxidation were enhanced in LONP1 in failing heart mitochondria.…”

Section: Discussionsupporting

confidence: 92%

Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Hoshino

Okawa

Ariyoshi

et al. 2014

Circ: Heart Failure

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Background— Mitochondrial compromise is a fundamental contributor to heart failure. Recent studies have revealed that several surveillance systems maintain mitochondrial integrity. The present study evaluated the role of mitochondrial AAA+ protease in a mouse model of pressure overload heart failure. Methods and Results— The fluorescein isothiocyanate casein assay and immunoblotting for endogenous mitochondrial proteins revealed a marked reduction in ATP-dependent proteolytic activity in failing heart mitochondria. The level of reduced cysteine was decreased, and tyrosine nitration and protein carbonylation were promoted in Lon protease homolog (LONP1), the most abundant mitochondrial AAA+ protease, in heart failure. Comprehensive analysis revealed that electron transport chain protein levels were increased even with a reduction in the expression of their corresponding mRNAs in heart failure, which indicated decreased protein turnover and resulted in the accumulation of oxidative damage in the electron transport chain. The induction of mitochondria-targeted human catalase ameliorated proteolytic activity and protein homeostasis in the electron transport chain, leading to improvements in mitochondrial energetics and cardiac contractility even during the late stage of pressure overload. Moreover, the infusion of mitoTEMPO, a mitochondria-targeted superoxide dismutase mimetic, recovered oxidative modifications of LONP1 and improved mitochondrial respiration capacity and cardiac function. The in vivo small interfering RNA repression of LONP1 partially canceled the protective effects of mitochondria-targeted human catalase induction and mitoTEMPO infusion. Conclusions— Oxidative post-translational modifications attenuate mitochondrial AAA+ protease activity, which is involved in impaired electron transport chain protein homeostasis, mitochondrial respiration deficiency, and left ventricular contractile dysfunction. Oxidatively inactivated proteases may be an endogenous target for mitoTEMPO treatment in pressure overload heart failure.

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Section: Discussionsupporting

confidence: 92%

Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Hoshino

Okawa

Ariyoshi

et al. 2014

Circ: Heart Failure

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“…Furthermore, animal studies using experimental models of hypertension suggested that mitochondrial dysfunction (ie, decreased expression of mitochondrial components and defects in respiratory complexes) and increased oxidative stress result in impaired oxidative capacity and reduced mitochondrial ATP production. 9,10 Importantly, in these animals, the mitochondrial dysfunction and the reduced oxidative capacity were present before the development of hypertension, suggesting a possible role of these processes to the pathogenesis of hypertension. 11 However, information on skeletal muscle microvascular alterations and oxidative capacity in hypertension has been obtained mainly from animal models or ex vivo from human biopsies.…”

mentioning

confidence: 87%

“…In agreement, a study in spontaneously hypertensive rats showed that alterations in mitochondrial enzymes in cardiac muscle preceded the clinical manifestation of hypertension. 9 Future studies should explore whether oxidative capacity dysfunctions in hypertensives could be reversed with appropriate pharmacotherapy as animals studies suggested that treatment with renin-angiotensin system inhibitors (angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors) can upregulate mitochondrial biogenesis and stimulate mitochondrial protein production. 34,35 Our findings also emphasize the importance of exercise training in hypertension because enhancement of mitochondrial function through improvements in fitness can cause BP reductions and improve patient outcomes.…”

Section: Muscle Oxidative Capacity and Microvascular Reactivitymentioning

confidence: 99%

Impaired Muscle Oxygenation and Elevated Exercise Blood Pressure in Hypertensive Patients

et al. 2017

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E ssential hypertension is characterized by sustained elevations of blood pressure (BP) that can lead to target organ damage and an increased risk for cardiovascular disease. 1Potential life-threatening outcomes of hypertension, such as stroke, renal insufficiency, and cardiac hypertrophy, had been initially perceived as a result of macrovascular alterations. These macrovascular events, however, do not occur independently of microvascular derangement. [2][3][4] Studies have shown that alterations in microvascular structure (rarefaction), vasomotor tonus (enhanced vasoconstriction or blunted vasodilation), and endothelial dysfunction are principal processes in the pathogenesis of hypertension and are evident in several organs/tissue types. [5][6][7][8] In the skeletal muscle, microvascularization is important for oxygen and nutrient supply and for effective metabolite clearance. Studies in hypertension have shown structural or functional impairments in the microvasculature within skeletal muscles, 8 implying a reduced capacity for oxygen delivery and exchange. Furthermore, animal studies using experimental models of hypertension suggested that mitochondrial dysfunction (ie, decreased expression of mitochondrial components and defects in respiratory complexes) and increased oxidative stress result in impaired oxidative capacity and reduced mitochondrial ATP production.9,10 Importantly, in these animals, the mitochondrial dysfunction and the reduced oxidative capacity were present before the development of hypertension, suggesting a possible role of these processes to the pathogenesis of hypertension.11 However, information on skeletal muscle microvascular alterations and oxidative Abstract-This study examined in vivo (1) skeletal muscle oxygenation and microvascular function, at rest and during handgrip exercise, and (2) their association with macrovascular function and exercise blood pressure (BP), in newly diagnosed, never-treated patients with hypertension and normotensive individuals. Ninety-one individuals (51 hypertensives and 40 normotensives) underwent office and 24-hour ambulatory BP, arterial stiffness, and central aortic BP assessment, followed by a 5-minute arterial occlusion and a 3-minute submaximal handgrip exercise. Changes in muscle oxygenated and deoxygenated hemoglobin and tissue oxygen saturation were continuously monitored by nearinfrared spectroscopy and beat-by-beat BP by Finapres. Hypertensives had higher (P<0.001) central aortic BP and pulse wave velocity versus normotensives and exhibited (1) a blunted tissue oxygen saturation response during occlusion, with slower (P=0.006) deoxygenation rate, suggesting reduced muscle oxidative capacity, and (2) a slower reoxygenation rate and blunted hyperemic response (P<0.05), showing reduced microvascular reactivity. Muscle oxygenation responses were correlated with aortic systolic and pulse pressure and augmentation index (P<0.05; age and body mass index (BMI) adjusted). When exercising at the same submaximal intensity, hypertensives required a sig...

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“…13 A combined proteomic and metabolomic analysis has been carried out in murine hearts to obtain mechanistic insights of protein kinase C epsilon (PKCϵ)-mediated cardioprotection.…”

Section: Gel-based Quantificationmentioning

confidence: 99%

“…12 Meng et al applied 2D-DIGE in combination with matrix-assisted laser desorption/ionization (MALDI)-time of flight/time of flight MS to identify alterations in mitochondrial enzymes that contribute to cardiac hypertrophy in spontaneously hypertensive rats. 13 A combined proteomic and metabolomic analysis has been carried out in murine hearts to obtain mechanistic insights of protein kinase C epsilon (PKCϵ)-mediated cardioprotection.…”

Section: Gel-based Quantificationmentioning

confidence: 99%

Quantitative Mass Spectrometry-Based Approaches in Cardiovascular Research

Mirza¹

2012

Circ Cardiovasc Genet

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ProteomicsC ardiovascular proteomics is a rapidly growing field, especially with the emergence of high-throughput mass spectrometry-based techniques. After the identification of proteins in a given sample, researchers are keen to find out how much of the protein is present, especially in a disease or a given state. Though challenging, over the past few years, several approaches have been established to quantify proteins from cells or tissues at a given state. In this review, we focus on mass spectrometry -based quantitative approaches for both large-scale and targeted proteomic analyses, which can be used in cardiovascular research. Several strategies using labeling and label-free approaches for both relative and absolute quantification (AQUA) have been established to meet the requirements of the researcher. Each of these methods has its own merits and limitations. We will discuss the methods that researchers can opt for to address the biological questions related to cardiovascular research.Cardiovascular proteomics is the branch of proteomics specifically applied to heart and vasculature. The field of proteomics has recently gained greater importance based on its potential to unravel the complex physiological and biochemical mechanisms and pathways in organisms and cells at the molecular level. The goal is to identify proteins that generate/mediate disease process, thereby, opening avenues to new diagnostics and therapeutic strategies. Proteins are much closer to the actual disease process, in most cases, than parent genes. They are the ultimate regulators of cell functions, and the vast majorities serve as drug targets. Differential protein expression analysis, by measuring the upregulated or downregulated proteins in disease state as compared with the normal healthy condition, is vital to understand the disease mechanism.In conjunction with various separation techniques, mass spectrometry (MS)-based methods evolved as the best techniques for the comprehensive characterization of proteins. 1,2After the initial protein identification, a more challenging approach in proteomics is the quantification of the proteins identified.3 Various methods of quantification by MS have been developed recently, for both relative and absolute measurements (Figure 1), and the technology is still expanding to find better and more efficient quantification approaches. This, in turn, is facilitated by the advancements in the MS instrumentation, including powerful analyzers and fragmentation technology. Most of the quantification methods are based on measurements at peptide level and fall under the bottom-up proteomics approach. In this review article, we will outline various MS-based approaches available for measuring the variation in protein abundances and how these techniques are playing a key role in cardiovascular research. Gel-Based QuantificationSeparation of proteins by polyacrylamide gel electrophoresis, followed by MS analysis, has been a common practice in proteomics. With the advent of 2D gel electrophoresis, quantificatio...

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Alterations of Mitochondrial Enzymes Contribute to Cardiac Hypertrophy before Hypertension Development in Spontaneously Hypertensive Rats

Cited by 44 publications

References 75 publications

Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Impaired Muscle Oxygenation and Elevated Exercise Blood Pressure in Hypertensive Patients

Quantitative Mass Spectrometry-Based Approaches in Cardiovascular Research

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