Molecular Abnormalities in Cardiomyopathy1

Dhalla, N.S.; Sulakhe, Prakash V.; Fedelesová, M; Yates, J. C.

doi:10.1159/000395542

Cited by 31 publications

(6 citation statements)

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“…Ultrastructural studies have shown that the initial events include cell necrosis and granular calcium deposition in or around the mitochondria (1)(2)(3). The pivotal role of intracellular calcium concentrations for cell injury and necrosis has been established (4,5) and recent data also suggest the involvement of cellular calcium homeostasis in the pathogenesis of chronic myocarditis and cardiomyopathy (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

A locus on chromosome 7 determines myocardial cell necrosis and calcification (dystrophic cardiac calcinosis) in mice.

Ivandic

Qiao

Machleder

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Calcium deposition at sites of inflammation and necrosis is a fundamental but poorly understood element of the response of tissue to injury. It is evident in clinical diseases, including atherosclerosis and cardiac valve sclerosis, in which chronic inflammation or degenerative process with cell death is involved. In the presence of normal calcium and phosphate serum concentrations, such calcification is usually termed dystrophic calcification or calcinosis. Ultrastructural studies have shown that the initial events include cell necrosis and granular calcium deposition in or around the mitochondria (1-3). The pivotal role of intracellular calcium concentrations for cell injury and necrosis has been established (4, 5) and recent data also suggest the involvement of cellular calcium homeostasis in the pathogenesis of chronic myocarditis and cardiomyopathy (6-8).Age-related spontaneous dystrophic cardiac calcinosis (DCC) occurs in several inbred strains of mice, including BALB/c, DBA/2, and C3H; DCC may even lead to congestive heart failure in older animals (9-12). Apart from age and genetic background, other factors including infectious agents (13-15), sex (9, 12), hormonal status (9,(16)(17)(18), and diet (1, 9, 19-21) can markedly influence the time of onset and the severity of DCC. The factors involved in the various etiologies of DCC are different, yet a common element of each is cell injury, necrosis, and subsequent calcium deposition. The typical pattern of susceptibility to DCC was also observed following a standardized myocardial freeze-thaw injury, suggesting a common genetic basis independent from the nature of the etiology (22).We now report the mapping of a major gene determining DCC, designated Dyscalc, on proximal mouse chromosome 7. The locus was identified by quantitative trait locus (QTL) analysis of an F2 intercross between the susceptible strain C3H/HeJ and the resistant strain C57BL/6J using a complete linkage map approach. The significance of the QTL results was tested by permutation analysis and the map position was further confirmed by analysis of a set of recombinant inbred (RI) strains derived from these progenitor strains. The results have implications for the understanding of cell injury and necrosis in myocardial and cardiovascular diseases. MATERIALS AND METHODSAnimals. All mice were obtained from The Jackson Laboratory. An F2 intercross between inbred strains C57BL/6J and C3H/HeJ was constructed in our laboratory; only female progeny (n = 197) were included in the studies to eliminate gender differences as a potential confounder. All animals were maintained in pathogen-free facilities on a 12-hr light/12-hr dark cycle with free access to water and food throughout the experimental period. At 3 months of age, mice were placed on a high-fat, high-cholesterol diet (TD 90221; Harlan-Teklad, Madison, WI) to accelerate DCC (23). After 8 weeks of high-fat diet, mice were sacrificed by cervical dislocation.Histological Analyses. After the mice were killed, the heart and proximal aorta were exci...

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Section: Introductionmentioning

confidence: 99%

A locus on chromosome 7 determines myocardial cell necrosis and calcification (dystrophic cardiac calcinosis) in mice.

Ivandic

Qiao

Machleder

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…The calcium transporting abilities of these subcellular fractions obtained from rat isolated hearts perfused with these P-adrenoceptor blocking agents were also examined to test if these subcellular effects of the drugs are associated with functional changes in the myocardium. It should be noted here that both sarcoplasmic reticulum and mitochondria are considered to regulate intracellular calcium and subsequently myocardial function (Harigaya & Schwartz, 1969;Dhalla, Sulakhe, Fedelesova & Yates, 1974) …”

Section: Introductionmentioning

confidence: 99%

Comparison of the Actions of Acebutolol, Practolol and Propranolol on Calcium Transport by Heart Microsomes and Mitochondria

Dhalla

Lee

1976

British J Pharmacology

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I The effects of acebutolol, practolol and propranolol (0.5-3 mM) on calcium uptake, calcium binding and ATPase activities of the rabbit and rat heart microsomal and mitochondrial fractions were investigated. 2 Dose-response and time course experiments revealed that propranolol greatly inhibited microsomal and mitochondrial calcium uptake whereas both acebutolol and practolol showed slight depressant effects. 3 The ATPase activities of microsomal and mitochondrial fractions were decreased by acebutolol, practolol and propranolol; however, the latter agent was more effective than the other two. 4 The inhibitory effects of acebutolol, practolol and propranolol on mitochondria and microsomes were not antagonized by adrenaline. 5Propranolol decreased calcium binding by the microsomal fraction only, whereas acebutolol and practolol had no effect on microsomal or mitochondrial calcium binding. 6 The sensitivity of the rabbit heart subcellular fractions to the /3-adrenoceptor blocking drugs was similar to that of the rat heart; however, the calcium uptake and ATPase activities of microsomes were more sensitive to propranolol than mitochondria in both species. 7 Perfusion of rat hearts with 0.2-1 mM propranolol decreased contractile force, and microsomal and mitochondrial fractions obtained from these hearts accumulated less calcium in comparison to the control. On the other hand, acebutolol and practolol (0.2-1 nM) had no appreciable effects on contractile force or subcellular fractions under similar conditions. 8 The negative inotropic effect of propranolol may partly be due to its inhibitory actions on calcium transport by subcellular organelles of the myocardium; the depressant action of propranolol on calcium transport is unlikely to be due to its,B-adrenoceptor blocking property.

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“…According to current concepts of muscle contraction and relaxation (Ebashi & Endo, 1968;Martonosi, 1972;Dhalla et al, 1974), the intracellular concentration of ionized calcium is increased mainly as a result of release from the sarcoplasmic reticulum upon depolarization. This increase in calcium releases the inhibition of the troponin-tropomyosin system and activates myofibrillar ATPase, thus providing energy for contraction due to sliding of the actin and myosin filaments.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study we offer our findings on various membrane systems such as sarcolemma, sarcotubular membranes and mitochondria, as well as myofibrils in myopathic skeletal muscle. These cellular structures are considered to be directly or indirectly involved in determining muscle function and metabolism (Ebashi & Endo, 1968;Martonosi, 1972;Dhalla, Sulakhe, Fedelesova & Yates, 1974). Thus any abnormality in sarcolemmal, sarcotubular, mitochondrial or myofibrillar function would indicate an important biochemical difference in hamster myopathy.…”

Section: Introductionmentioning

confidence: 99%

Defective Membrane Systems in Dystrophic Skeletal Muscle of the UM-X7.1 Strain of Genetically Myopathic Hamster

et al. 1975

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1. The function of mitochondria, sarcotubular membranes (heavy microsomes), sarcolemma and myofibrils from the hind-leg skeletal muscle of about 60- and 150-day-old normal and myopathic (UM-X7.1) hamsters was examined. 2. The mitochondrial calcium uptake as well as mitochondrial phosphorylation and respiratory rates were lower in 60-day-old myopathic skeletal muscle, unlike 150-day-old myopathic animals, when pyruvate-malate and glutamate-malate were used as substrates. However, mitochondria from 150-day-old myopathic animals showed depressed glutamate-dependent respiratory and phosphorylation rates and succinate-supported initial rate of calcium uptake. 3. The microsomal calcium-uptake, but not calcium-binding, and Ca2+-stimulated adenosine triphosphatase (ATPase) activity of the 150-day-old myopathic skeletal muscle were lower than the control values. Although microsomal calcium-binding, calcium-uptake and ATPase activities of the 60-day-old myopathic muscle were not depressed significantly, the initial rate of calcium uptake was less than the control. 4. The sarcolemmal Ca2+-ATPase, but not Mg2+-ATPase or Na+ +K+-ATPase, activity was higher in 60-day-old myopathic muscle whereas the activities of all these enzymes from 150-day-old myopathic animals were higher than the control. On the other hand, the Na+ +K+-ATPase activities from 60- and 150-day-old myopathic animals were inhibited by ouabain to a lesser extent in comparison with the respective control values. 5. The myofibrillar Ca2+-ATPase and Mg2+-ATPase activities as well as inhibition of Mg2+-ATPase due to Na+ and K+ in myopathic muscle were no different from the control values. 6. The results reported here give further support to the view that different membrane systems of the dystrophic muscle are defective.

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Molecular Abnormalities in Cardiomyopathy1

Cited by 31 publications

References 0 publications

A locus on chromosome 7 determines myocardial cell necrosis and calcification (dystrophic cardiac calcinosis) in mice.

A locus on chromosome 7 determines myocardial cell necrosis and calcification (dystrophic cardiac calcinosis) in mice.

Comparison of the Actions of Acebutolol, Practolol and Propranolol on Calcium Transport by Heart Microsomes and Mitochondria

Defective Membrane Systems in Dystrophic Skeletal Muscle of the UM-X7.1 Strain of Genetically Myopathic Hamster

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