Pacing-Induced Heart Failure in Dogs Enhances the Expression of p53 and p53-Dependent Genes in Ventricular Myocytes

Leri, Annarosa; Liu, Yu; Malhotra, Ashwani; Li, Qiong; Stiegler, Peter; Claudio, Pier Paolo; Giordano, Antonio; Kajstura, Jan; Hintze, Thomas H.; Anversa, Piero

doi:10.1161/01.cir.97.2.194

Cited by 105 publications

(78 citation statements)

References 56 publications

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“…Corkscrew electrodes attached to a pacemaker were inserted into young mongrel dogs (6)(7)(8)15). Hearts were paced at 210 beats per min for 3 weeks and at 240 for another week.…”

Section: Methodsmentioning

confidence: 99%

“…Eight dogs were used as controls. After collection of hemodynamic data (6)(7)(8)15), hearts were arrested in diastole, and each left ventricle was separated in two parts, one for myocyte isolation and biochemistry and the other for formalin fixation and cytochemistry.…”

Section: Methodsmentioning

confidence: 99%

“…Myocytes were dissociated as described (6)(7)(8)16). The number of myocytes varied from 7.3 ϫ 10 6 to 4.5 ϫ 10 6 ͞g of myocardium in control and paced hearts, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The number of myocytes varied from 7.3 ϫ 10 6 to 4.5 ϫ 10 6 ͞g of myocardium in control and paced hearts, respectively. Nonmyocytes accounted for 2-3% of the cell population (6)(7)(8)16 (17). PCR products were separated on 12% polyacrylamide gel.…”

Section: Methodsmentioning

confidence: 99%

“…The discovery of neuronal regeneration in the human brain (3) and myocyte cytokinesis in the human heart (4, 5) has not changed the view of most investigators and clinicians in the cardiovascular field. To improve understanding the biology of the heart and obtain supportive evidence of myocyte division, three indices of cell proliferation were analyzed in dogs affected by a disease state, mimicking dilated cardiomyopathy in patients (6)(7)(8). These markers consisted of telomerase activity, Ki67 labeling, and identification of cycling telomerase competent cells.…”

mentioning

confidence: 99%

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Telomerase expression and activity are coupled with myocyte proliferation and preservation of telomeric length in the failing heart

Leri

Barlucchi

Limana

et al. 2001

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

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The role and even the existence of myocyte proliferation in the adult heart remain controversial. Documentation of cell cycle regulators, DNA synthesis, and mitotic images has not modified the view that myocardial growth can only occur from hypertrophy of an irreplaceable population of differentiated myocytes. To improve understanding the biology of the heart and obtain supportive evidence of myocyte replication, three indices of cell proliferation were analyzed in dogs affected by a progressive deterioration of cardiac performance and dilated cardiomyopathy. The magnitude of cycling myocytes was evaluated by the expression of Ki67 in nuclei. Ki67 labeling of left ventricular myocytes increased 5-fold, 12-fold, and 17-fold with the onset of moderate and severe ventricular dysfunction and overt failure, respectively. Telomerase activity in vivo is present only in multiplying cells; this enzyme increased 2.4-fold and 3.1-fold in the decompensated heart, preserving telomeric length in myocytes. The contribution of cycling myocytes to telomerase activity was determined by the colocalization of Ki67 and telomerase in myocyte nuclei. More than 50% of Ki67-positive cells expressed telomerase in the overloaded myocardium, suggesting that these myocytes were the morphological counterpart of the biochemical assay of enzyme activity. Moreover, we report that 20 -30% of canine myocytes were telomerase competent, and this value was not changed by cardiac failure. In conclusion, the enhanced expression of Ki67 and telomerase activity, in combination with Ki67-telomerase labeling of myocyte nuclei, support the notion that myocyte proliferation contributes to cardiac hypertrophy of the diseased heart.

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“…Corkscrew electrodes attached to a pacemaker were inserted into young mongrel dogs (6)(7)(8)15). Hearts were paced at 210 beats per min for 3 weeks and at 240 for another week.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Myocytes were dissociated as described (6)(7)(8)16). The number of myocytes varied from 7.3 ϫ 10 6 to 4.5 ϫ 10 6 ͞g of myocardium in control and paced hearts, respectively.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Telomerase expression and activity are coupled with myocyte proliferation and preservation of telomeric length in the failing heart

Leri

Barlucchi

Limana

et al. 2001

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

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Elevated DNase activity and caspase expression in association with apoptosis in failing ischemic sheep left ventricles

et al. 1999

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We examined the DNase activity as well as the expression of the caspases in left ventricles of failing sheep hearts and compared it with samples from normal controls. The sheep model of chronic ischemic heart failure was developed by intracoronary microembolisation. Moderate heart failure was defined as a decrease of left ventricular (LV) ejection fraction (EF) to 35% or less and was stable for four weeks after the last embolisation. The failing hearts were harvested from these animals six months later. Bovine pancreas DNase I was used as a standard for the DNase zymograms. In normal sheep left ventricles, a low level of the DNase I‐like activity was detected (1.16 ± 0.17 pg/100 μg protein, n = 20), whereas it was elevated (3.64 ± 0.49 pg/100 μg, n = 32, p < 0.001) in the ischemic failing LV samples. The identity of the DNase in sheep is yet to be fully characterised. However, we also detected the expression of caspase‐2 and caspase‐3 by Western blotting. There was a 2.2‐fold increased expression of caspase‐2 p < 0.001= and a 2.6‐fold increased expression of caspase‐3 (p < 0.001) in failing left ventricles compared to normal samples.

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Changes in myocardial protein expression in pacing-induced canine heart failure

Heinke

Wheeler²,

Yan³

et al. 1999

Electrophoresis

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Canine rapid ventricular pacing produces a low output cardiomyopathic state which is similar to dilated cardiomyopathy. In this study dogs were paced at 245 beats per minute (bpm) for 3—4 weeks until signs of heart failure were apparent. Unpaced dogs were used as controls. A previous study identified myocardial protein changes in the pH region 4—7 following ventricular pacing by using two‐dimensional electrophoresis (2‐DE) (Heinke et al., Electrophoresis 1998 19, 2021—2030). Many of these proteins were associated with mitochondria, energy metabolism within the cardiomyocyte, the cytoskeleton and calcium cycling. The present study aimed to examine the proteins migrating in the more basic region of the 2‐DE pattern using immobilised pH gradient 3—10 strips to separate myocardial proteins. The expression of 31 proteins was altered in the paced myocardium: 21 were decreased and 10 increased. Following the identification of 23 of these spots by either amino acid compositional analysis or peptide mass fingerprinting or a combination of both, we confirm that many of the proteins whose expression is altered following ventricular pacing are associated with the mitochondria and energy production within the cardiomyocyte, including creatine kinase M, triosephosphate isomerase, phosphoglycerate mutase, cytochrome c oxidase, cytochrome b5, hydroxymethyl glutaryl CoA synthase, myoglobin, and 3,2‐trans‐enoyl‐CoA transferase. Additionally, the cytoskeletal protein actin was increased in the paced hearts. These results strongly support the notion that energy production is impaired and mitochondrial dysfunction is involved in the development of heart failure in the paced dog.

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Pacing-Induced Heart Failure in Dogs Enhances the Expression of p53 and p53-Dependent Genes in Ventricular Myocytes

Cited by 105 publications

References 56 publications

Telomerase expression and activity are coupled with myocyte proliferation and preservation of telomeric length in the failing heart

Telomerase expression and activity are coupled with myocyte proliferation and preservation of telomeric length in the failing heart

Elevated DNase activity and caspase expression in association with apoptosis in failing ischemic sheep left ventricles

Changes in myocardial protein expression in pacing-induced canine heart failure

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