Acute myocardial infarction is the second cause of mortality in most countries, therefore, it is important to know the evolution and sequence of the physiological and biochemical changes involved in this pathology. This study attempts to integrate these changes and to correlate them in a long-term model (96 h) of isoproterenol-induced myocardial cell damage in the rat. We achieved an infarct-like damage in the apex region of the left ventricle, occurring 12-24 h after isoproterenol administration. The lesion was defined by histological criteria, continuous telemetric ECG recordings, and the increase in serum marker enzymes, specific for myocardial damage. A distinction is made among preinfarction, infarction, and postinfarction. Three minutes after drug administration, there was a 60% increase in heart rate and a lowering of blood pressure, resulting possibly in a functional ischemia. Ultrastructural changes and mitochondrial swelling were evident from the first hour of treatment, but functional alterations in isolated mitochondria, such as decreases in oxygen consumption, respiratory quotient, ATP synthesis, and membrane potential, were noticed only 6 h after drug administration and lasted until 72 h later. Mitochondrial proteins decreased after 3 h of treatment, reaching almost a 50% diminution, which was maintained during the whole study. An energy imbalance, reflected by a decrease in energy charge and in the creatine phosphate/creatine ratio, was observed after 30 min of treatment; however, ATP and total adenine nucleotides diminished clearly only after 3 h of treatment. All these alterations reached a maximum at the onset of infarction and were accompanied by damage to the myocardial function, drastically decreasing left ventricular pressure and shortening the atrioventricular interval. During postinfarction, a partial recovery of energy charge, creatine phosphate/creatine ratio, membrane potential, and myocardial function occurred, but not of mitochondrial oxygen consumption, rate of ATP synthesis, total adenine nucleotides, or mitochondrial proteins. Interesting correlations of the sequential changes in heart and mitochondrial functions with energy metabolism were obtained at different stages of the isoproterenol-induced cardiotoxicity. These correlations could be useful to study and understand the cellular events involved in this pathology.
SUMMARY:We have proposed that controlled peroxidative modifications of membranes could be playing a role in the early steps of liver regeneration. Hence, lipid peroxidation (LP) was modified in vivo by treatment with vitamin E in rats subjected to partial hepatectomy (PH), and its influence on liver regeneration was evaluated. Our results, using several methods to monitor LP, indicate that vitamin E administration promoted a decreased LP rate in liver subcellular membranes. Vitamin E drastically diminished cytosolic LP, shifting earlier increased LP in plasma membranes, and promoted a higher increase of nuclear LP in animals subjected to PH. Pretreatment with vitamin E induced a striking reduction of liver mass recovery and nuclear bromodeoxyuridine labeling (clearly shown at 24 hours after surgery), as well as promoted a decreased expression of cyclin D1 and of the proliferating cell nuclear antigen after PH. These effects seem to lead to a decreased mitotic index at 48 hours after PH. Vitamin E pretreatment also diminished PH-induced hypoglycemia but elevated serum bilirubin level, which was not observed in PH animals without vitamin treatment. In conclusion, an enhanced but controlled LP seems to play a critical role during the early phases of liver regeneration. Decreasing magnitude or time course of the PH-promoted enhanced LP (at early post-PH stages) by in vivo treatment with vitamin E could promote an early termination of preparative cell events, which lead to the replicative phase, during PH-promoted liver proliferation. The latter could have a significant implication in the antitumorigenic effect ascribed to the treatment with vitamin E. (Lab Invest 2003, 83:1669 -1679.
Hepatic fibrosis underlies most types of chronic liver diseases and is characterized by excessive deposition of extracellular matrix (ECM), altered liver architecture, and impaired hepatocyte proliferation; however, the fibrotic liver can still regenerate after partial hepatectomy (PH). Therefore, the present study was aimed at addressing whether a PH-induced regeneration normalizes ECM turnover and the possible involvement of hepatic stellate cells (HSC) during resolution of a pre-established fibrosis. Male Wistar rats were rendered fibrotic by intraperitoneal administration of swine serum for 9 weeks and subjected afterwards to 70% PH or sham-operation. Histological and morphometric analyses were performed, and parameters indicative of cell proliferation, collagen synthesis and degradation, and activation of HSC were determined. Liver collagen content was reduced to 75% after PH in cirrhotic rats when compared with sham-operated cirrhotic rats. The regenerating fibrotic liver oxidized actively free proline and had diminished transcripts for alpha-1 (I) collagen mRNA, resulting in decreased collagen synthesis. PH also increased collagenase activity, accounted for by higher amounts of pro-MMP-9, MMP-2, and MMP-13, which largely coincided with a lower expression of TIMP-1 and TIMP-2. Therefore, an early decreased collagen synthesis, mild ECM degradation, and active liver regeneration were followed by higher collagenolysis and limited deposition of ECM, probably associated with increased mitochondrial activity. Activated HSC readily increased during liver fibrosis and remained activated after liver regeneration, even during fibrosis resolution. In conclusion, stimulation of liver regeneration through PH restores the balance in ECM synthesis/degradation, leading to ECM remodeling and to an almost complete resolution of liver fibrosis. As a response to the regenerative stimulus, activated HSC seem to play a controlling role on ECM remodeling during experimental cirrhosis in rats. Therefore, pharmacological approaches for the resolution of liver fibrosis by blocking HSC activation should also evaluate possible effects on liver cell proliferation.
The dog is considered the main domestic reservoir for Trypanosoma cruzi infection and a suitable experimental animal model to study the pathological changes during the course of Chagas disease (CD). Vaccine development is one of CD prevention methods to protect people at risk. Two plasmids containing genes encoding a trans-sialidase protein (TcSP) and an amastigote-specific glycoprotein (TcSSP4) were used as DNA vaccines in a canine model. Splenomegaly was not found in either of the recombinant plasmid-immunized groups; however, cardiomegaly was absent in animals immunized only with the plasmid containing the TcSSP4 gene. The inflammation of subendocardial and myocardial tissues was prevented only with the immunization with TcSSP4 gene. In conclusion, the vaccination with these genes has a partial protective effect on the enlargement of splenic and cardiac tissues during the chronic CD and on microscopic hearth damage, since both plasmids prevented splenomegaly but only one avoided cardiomegaly, and the lesions in heart tissue of dog immunized with plasmid containing the TcSSP4 gene covered only subepicardial tissue.
Acute myocardial infarction is the second cause of mortality in most countries, therefore, it is important to know the evolution and sequence of the physiological and biochemical changes involved in this pathology. This study attempts to integrate these changes and to correlate them in a long-term model (96 h) of isoproterenol-induced myocardial cell damage in the rat. We achieved an infarct-like damage in the apex region of the left ventricle, occurring 12-24 h after isoproterenol administration. The lesion was defined by histological criteria, continuous telemetric ECG recordings, and the increase in serum marker enzymes, specific for myocardial damage. A distinction is made among preinfarction, infarction, and postinfarction. Three minutes after drug administration, there was a 60% increase in heart rate and a lowering of blood pressure, resulting possibly in a functional ischemia. Ultrastructural changes and mitochondrial swelling were evident from the first hour of treatment, but functional alterations in isolated mitochondria, such as decreases in oxygen consumption, respiratory quotient, ATP synthesis, and membrane potential, were noticed only 6 h after drug administration and lasted until 72 h later. Mitochondrial proteins decreased after 3 h of treatment, reaching almost a 50% diminution, which was maintained during the whole study. An energy imbalance, reflected by a decrease in energy charge and in the creatine phosphate/creatine ratio, was observed after 30 min of treatment; however, ATP and total adenine nucleotides diminished clearly only after 3 h of treatment. All these alterations reached a maximum at the onset of infarction and were accompanied by damage to the myocardial function, drastically decreasing left ventricular pressure and shortening the atrioventricular interval. During postinfarction, a partial recovery of energy charge, creatine phosphate/creatine ratio, membrane potential, and myocardial function occurred, but not of mitochondrial oxygen consumption, rate of ATP synthesis, total adenine nucleotides, or mitochondrial proteins. Interesting correlations of the sequential changes in heart and mitochondrial functions with energy metabolism were obtained at different stages of the isoproterenol-induced cardiotoxicity. These correlations could be useful to study and understand the cellular events involved in this pathology.
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