Prevention of Cardiac Hypertrophy in Experimental Chronic Renal Failure by Long-Term ACE Inhibitor Administration: Potential Role of Lysosomal Proteinases

Suzuki, Hiroaki; Schaefer, Liliana; Li, Hong; Schaefer, Roland M.; Dämmrich, J.; Teschner, Markus; Heidland, A.

doi:10.1159/000168817

Cited by 31 publications

(24 citation statements)

References 25 publications

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“…As was clearly shown previously [33,34], enalapril effectively suppressed the development of the cardiac hypertrophy in this uremic animal model. Although no statistical significance was observed, the calcimimetic also showed a moderate suppressive effect.…”

Section: Discussionsupporting

confidence: 87%

Effects of Calcimimetic Combined with an Angiotensin-Converting Enzyme Inhibitor on Uremic Cardiomyopathy Progression

Mizobuchi

Ogata²,

Hosaka³

et al. 2011

Am J Nephrol

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Background/Aims: Angiotensin-converting enzyme (ACE) inhibitors have cardioprotective properties and functional calcium-sensing receptors express in cardiac myocytes. Methods: Rats were made uremic by 5/6 nephrectomy and treated as follows: uremic rats were fed on a regular diet (UC), uremic + enalapril (E), uremic + calcimimetic agent R-568 (R-568), and uremic + enalapril + R-568 (E+R-568). A group of normal rats served as controls (NC). Results: Blood pressure (BP) and left ventricle mass were elevated significantly in the UC and R-568 groups compared with those in the NC group, but were indistinguishable from normal controls in the E and E+R-568 groups. Cardiac fibrosis was significantly increased in the UC group compared with that in the NC group. This increase was significantly attenuated in the R-568 and E groups, and the attenuation was further enhanced in the E+R-568 group. Factors associated with cardiac hypertrophy such as proliferating cell nuclear antigen, cyclin D1, and cyclin D2, as well as factors associated with cardiac fibrosis such as type I collagen, fibronectin, and transforming growth factor-β1 were significantly increased in the UC group compared with those in the NC group. Monotherapy with R-568 or E attenuated this increase and the combination further attenuated these measures. Conclusions: Calcimimetics can suppress the progression of uremic cardiomyopathy and this effect is amplified when BP is controlled via renin-angiotensin system blockade.

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Section: Discussionsupporting

confidence: 87%

Effects of Calcimimetic Combined with an Angiotensin-Converting Enzyme Inhibitor on Uremic Cardiomyopathy Progression

Mizobuchi

Ogata²,

Hosaka³

et al. 2011

Am J Nephrol

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“…These adverse structural changes have been previously linked to changes in TGF-β expression. TGF-β [25,26,27,28,29] and decreased lysosomal cathepsin activity [30, 31] have previously been associated with the development of cardiac hypertrophy and fibrosis. Overexpression of TGF-β 1 in transgenic mice has been shown to lead to cardiac hypertrophy [29], while the development of fibrosis was decreased in heterozygous TGF-β 1 -deficient mice [45], highlighting the crucial fibrosis-promoting role of this cytokine.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to the kidney, associations between decreased activities of lysosomal cysteine proteinases and the development of cardiac hypertrophy and fibrosis have been established [30, 31]. ACE inhibition has been demonstrated to restore lysosomal cysteine proteinase cathepsin B activity in the heart [30], while ACE inhibition and angiotensin II receptor antagonism has been shown to successfully prevent or reverse cardiac hypertrophy and fibrosis [30,32,33,34,35,36,37,38,39]. …”

Section: Introductionmentioning

confidence: 99%

Hypertension-Mediated Albuminuria Is Associated with Reduced Lysosomal Activity in the Kidney and the Heart

2008

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Background: Recent studies suggest that expression of the transforming growth factor-β (TGF-β)-inducible gene-h3 (βig-h3) and its anti-lysosomal activity may be responsible for the development of albuminuria and cardiovascular disease associated with hypertension. Methods: We evaluated the proposed linkage using the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat models. The kidney and left ventricular weight/body weight ratios were measured and cardiac collagen deposition was analyzed by Masson’s trichrome stain. Renal and cardiac TGF-β₁ and βig-h3 expression were determined by real-time reverse transcription-polymerase chain reaction, and renal and cardiac cathepsin B and L activities were measured as an indicator of lysosomal proteolytic activity. Results: SHR exhibited increased levels of intact urinary albumin without significant change in total albumin (intact plus albumin-derived material) excretion. This was accompanied by renal hypertrophy, increased renal βig-h3 expression, and reduced renal cathepsin B and L activities. At the same time, increased cardiac TGF-β₁ and βig-h3 expression and reduced cardiac cathepsin B activity was identified in SHR in addition to cardiac hypertrophy and increased collagen deposition. All these changes could be ameliorated with ramipril treatment. Conclusions: These findings implicate for the first time βig-h3 expression and lysosomal activity as a key factor in the induction of albuminuria and cardiovascular disease associated with hypertension.

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“…Due to the influence of edema on body weight, patients with anasarca or localized noninflammatory edema were excluded, as were patients with signs of chronic hepatopathy (viral hepatitis, alcoholic hepatitis, or cirrhosis), glomerulopathy, and with obesity defined as a body mass index greater than 27kg/m 2 . Positive serological reactions for Chagas' disease and the presence of intracardiac thrombosis or pericarditis were also considered exclusion criteria, as was the presence of morphological renal signs suggestive of chronic renal insufficiency, which is a condition frequently associated with cardiomegaly 9 . The nutritional status was characterized by body mass index, which was calculated by dividing body weight in kilos by height in square meters (kg/m 2 ); individuals with body mass index <18.5kg/m 2 were considered malnourished 10 .…”

Section: Methodsmentioning

confidence: 99%

Heart Weight and Heart Weight/Body Weight Coefficient in Malnourished Adults

Cunha

Reis

et al. 2002

Arq. Bras. Cardiol.

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Objective -To compare the heart weight and the heart weight/body weight coefficient of adults with and without chronic malnutrition. Chronic malnutrition results from the inadequate intake of nutrients, with the predominance of catabolic processes over the anabolic ones, and the progressive wasting of fat and muscle protein body reserves. In adult individuals, chronic protein-calorie malnutrition manifests as progressive weight loss with hypofunction and hypotrophy of organs, such as the spleen, intestines, and kidneys 1 . Experiments with animals 2 and autopsies of malnourished children show that the heart undergoes hypotrophy proportional to the degree of weight loss 3,4 . Even though studies on heart morphometry and function of malnourished adults are rare 5 , experiments with animals suggest that the myocardium undergoes a milder wasting than striated skeletal muscles do, possibly due to the relative increase in vascularization and oxygenation of the myocardiocytes 6 . However, patients quite frequently develop tachycardia, hydric retention, and cardiac decompensation during nutritional therapy, and this phenomenon has been attributed to myocardial dysfunction associated with cardiac hypotrophy secondary to malnutrition 7 . The heart weight/body weight (HW/BW) coefficient, whose normal value is around 0.5±0.02, has been used for characterizing myocardial hypertrophy 8 and could be used for assessing myocardial hypotrophy. A study carried out by our group 8 , even though with other objectives, showed that individuals dying with cachexia had a HW/BW coefficient greater than normal. However, the relations between the HW/BW coefficient and other parameters of nutritional assessment, such as body weight, height, and body mass index, have not yet been established. Methods -In an initial case series of 210 autopsies performed in adults, we recorded body and heart weights and calculated the heart weight/body weight coefficients (HW/BW x 100Our hypothesis was that, due to the relative preservation of cardiac weight in relation to body mass index, malnourished adults would have a greater HW/BW coefficient than that of non-malnourished control individuals. The objective of our study was to compare heart weight and the HW/BW coefficient of adults with and without chronic malnutrition.

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Prevention of Cardiac Hypertrophy in Experimental Chronic Renal Failure by Long-Term ACE Inhibitor Administration: Potential Role of Lysosomal Proteinases

Cited by 31 publications

References 25 publications

Effects of Calcimimetic Combined with an Angiotensin-Converting Enzyme Inhibitor on Uremic Cardiomyopathy Progression

Effects of Calcimimetic Combined with an Angiotensin-Converting Enzyme Inhibitor on Uremic Cardiomyopathy Progression

Hypertension-Mediated Albuminuria Is Associated with Reduced Lysosomal Activity in the Kidney and the Heart

Heart Weight and Heart Weight/Body Weight Coefficient in Malnourished Adults

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