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Biomedical subjects

Peter Razeghi

Publications and source records attributed to Peter Razeghi.

At least 19 recordsLinked to original sources
PubMed2006

Mechanical unloading of the heart activates the calpain system.

The mechanism for the decrease in cardiomyocyte size with mechanical unloading is unknown. The calpain system regulates cardiomyocyte atrophy. We obtained samples from failing human hearts at the time of implantation and explantation of a left ventricular assist device. For mechanical unloading, we also heterotopically transplanted rat or mouse hearts for 1 week. The effect of calpain inhibition on cardiac atrophy was assessed in transplanted hearts overexpressing calpastatin. We measured transcript levels of calpain 1 and 2 in the human and the rodent model, as well as calpain activity, a calpain-specific degradation product and cardiomyocyte size in the two rodent models. Mechanical unloading of the failing human heart significantly increased calpain 2 gene expression. Transcript levels of calpain 1 and 2, calpain activity and a calpain-specific degradation product all significantly increased in the unloaded rat heart. Unexpectedly, in hearts of animals overexpressing calpastatin, cardiomyocyte size also decreased. Mechanical unloading of the mammalian heart activates the calpain system, although other proteolytic systems may compensate for decreased calpain activity when calpastatin is overexpressed.

Animals↗
PubMed2006

Induction of antioxidant gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species.

Ischemia and reperfusion (I/R) are characterized by oxidative stress as well as changes in the antioxidant enzymes of the heart. However, little is known about the transcriptional regulation of myocardial antioxidant enzymes in repetitive I/R and hibernating myocardium. In a mouse model of ischemic cardiomyopathy induced by repetitive I/R, we postulated that induction of antioxidant gene expression was dependent on reactive oxygen species (ROS). Repetitive closed-chest I/R (15 min) was performed daily in C57/BL6 mice and in mice overexpressing extracellular superoxide dismutase (EC-SOD). Antioxidant enzyme expression was measured at 3, 5, 7, and 28 days of repetitive I/R as well as 15 and 30 days after discontinuation of I/R. In order to determine whether ROS directly modulates antioxidant gene expression, transcript levels were measured in cardiomyocytes exposed to hydrogen peroxide. Repetitive I/R caused an early and sustained increase in glutathione peroxidase (GPX) transcript levels, while heme oxygenase-1 (HO-1) expression increased only after 7 days of repetitive I/R. Overexpression of EC-SOD prevented the upregulation of GPX and HO-1 transcript levels by repetitive I/R, suggesting that both genes are regulated by ROS. However, while HO-1 transcript levels increased in cardiomyocytes exposed to hydrogen peroxide, oxidative stress failed to induce the expression of GPX implying that ROS regulates GPX transcript levels only indirectly in repetitive I/R. In conclusion, repetitive I/R was associated with an early upregulation of GPX expression as well as a delayed increase of HO-1 transcript levels in the heart. The induction of both antioxidant genes was dependent on ROS, suggesting that alterations in redox balance mediate not only tissue injury but also components of "programmed cell survival" in hibernating myocardium.

Animals↗
PubMed2006

Atrophy, hypertrophy, and hypoxemia induce transcriptional regulators of the ubiquitin proteasome system in the rat heart.

BACKGROUND: In skeletal muscle, transcript levels of proteins regulating the ubiquitin proteasome system (UPS) increase with atrophy and decrease with hypertrophy. Whether the same is true for heart muscle is not known. AIM OF THE STUDY: We set out to characterize the transcriptional profile of regulators of the UPS during atrophy-, hypertrophy-, and hypoxia-induced remodeling of the heart. METHODS AND RESULTS: Cardiac atrophy was induced by heterotopic transplantation of the rat heart. Left ventricular hypertrophy was induced by banding of the ascending aorta in rats. To study the effects of hypoxemia on the left ventricle, rats were exposed to hypobaric hypoxia. Transcript levels of six known regulators of the UPS, ubiquitin B (UbB), the ubiquitin conjugating enzymes UbcH2 and E2-14kDa, the ubiquitin ligases Mafbx/Atrogin-1 and MuRF-1, and the proteasomal subunit PSMB4 were measured using quantitative RT-PCR. Unloading-induced atrophy increased mRNA levels of UbB and decreased levels of both ubiquitin ligases. Transcript levels of all UPS genes investigated increased in the hypertrophied and hypoxic heart (with the exception of E2-14kDa). CONCLUSIONS: Cardiac atrophy, hypertrophy, and hypoxemia all increase myocardial UbB expression, suggesting that UbB is a transcriptional marker for load-induced and hypoxia-mediated cardiac remodeling.

Animals↗
PubMed2006

Atrophic remodeling of the transplanted rat heart.

We have previously shown that the common feature of both pressure overload-induced hypertrophy and atrophy is a reactivation of the fetal gene program. Although gene expression profiles and signal transduction pathways in pressure overload hypertrophy have been well studied, little is known about the mechanisms underlying atrophic remodeling of the unloaded heart. Here, we induced atrophic remodeling by heterotopic transplantation of the rat heart. The activity parameters of three signal transduction pathways important in hypertrophy, i.e. mitogen-activated protein (MAP) kinase, mammalian target of rapamycin (mTOR), and Janus kinase/signal transducers and activators of transcription (JAK/STAT), were interrogated. Gene expression of upstream stimuli--insulin-like growth factor 1 (IGF-1) and fibroblast growth factor 2 (FGF-2)--and metabolic correlates, i.e. peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARalpha-regulated genes, of these pathways were also measured. In addition, we measured transcript levels of genes known to regulate skeletal muscle atrophy, all of which are negatively regulated by IGF-1 (Mafbx/Atrogin-1, MuRF-1). Atrophic remodeling of the heart was associated with increased expression of IGF-1 and FGF-2. Transcript levels of the nuclear receptor PPARalpha were decreased, as were the levels of PPARalpha-regulated genes. Furthermore, there was phosphorylation of ERK1, STAT3, and p70S6K with unloading. Consistent with the increase in IGF-1, we found a decrease in Mafbx/Atrogin-1 and MuRF-1 transcript levels. Rapamycin administration at 0.8 mg/kg/day for 7 days resulted in enhanced atrophy and attenuated the phosphorylation of ERK1, STAT3, and p70S6K without altering gene expression. We conclude that there is significant crosstalk between the mTOR, MAP kinase, and JAK/STAT signaling cascades. Furthermore, ubiquitin ligases, known to be essential for skeletal muscle atrophy, decrease in unloading-induced cardiac atrophy.

Animals↗
PubMed2006

Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart.

Mechanical unloading of the rat heart increases both protein synthesis and protein degradation. The transcriptional mechanism underlying increased protein synthesis during atrophic remodeling is not known. The aim of this study was to identify transcriptional regulators and the gene expression profile regulating protein synthesis in the unloaded rat heart and in the unloaded failing human heart. We measured DNA binding activity, transcript levels, and protein expression of transcriptional regulators of protein synthesis in a model of atrophic remodeling induced by heterotopic transplantation of the rat heart (duration 1 and 7 days). Using microarray analysis and quantitative RT-polymerase chain reaction, we found an increase in c-myc-regulated gene expression including an induction of ribosomal subunit messenger RNA's (RPS 10, RPL 21) and rRNA (18S). Consistent with the gene expression profile, DNA binding activity of c-myc and the nuclear protein concentration of its coactivator, upstream binding factor (UBF), increased in the atrophied heart whereas protein levels of the c-myc inhibitor MAD1 decreased. We found the same increase of ribosomal subunit messenger RNA and rRNA in 21 paired samples of failing human hearts obtained before and after left ventricular assist device treatment (mean duration: 157+/-31 days). In summary, mechanical unloading increases c-myc activity and c-myc-regulated gene expression in the rat heart. Changes in transcript levels of genes regulating ribosomal biogenesis in the unloaded rat heart resemble those found in the unloaded failing human heart. We concluded c-myc and c-myc-regulated gene expression are transcriptional regulators of protein synthesis during atrophic remodeling of the heart.

Animals↗
PubMed2006

Hypertrophy and atrophy of the heart: the other side of remodeling.

The size of a cardiomyocyte is determined by relative rates of protein synthesis and degradation. Signaling pathways regulating myocardial protein synthesis have been extensively investigated, not the least because in patients hypertrophy increases cardiovascular morbidity and mortality. Until now strategies to reverse hypertrophy have relied on the inhibition of prohypertrophic signaling pathways. Here we review signaling pathways of atrophy in the heart and we present evidence in support of the idea that activating proatrophic signaling pathways in the presence of prohypertrophic signaling may be an attractive strategy to reverse hypertrophy.

Animals↗
PubMed2005

The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling.

Although signaling mechanisms inducing cardiac hypertrophy have been extensively studied, little is known about the mechanisms that reverse cardiac hypertrophy. Here, we describe the existence of a similar Akt/forkhead signaling axis in cardiac myocytes in vitro and in vivo, which is regulated by insulin, insulin-like growth factor (IGF), stretch, pressure overload, and angiotensin II stimulation. FOXO3a gene transfer prevented both IGF and stretch-induced hypertrophy in rat neonatal cardiac myocyte cultures in vitro. Transduction with FOXO3a also caused a significant reduction in cardiomyocyte size in mouse hearts in vivo. Akt/FOXO signaling regulated the expression of multiple atrophy-related genes "atrogenes," including the ubiquitin ligase atrogin-1 (MAFbx). In cardiac myocyte cultures, transduction with constitutively active Akt or treatment with IGF suppressed atrogin-1 mRNA expression, whereas transduction with FOXO3a stimulated its expression. FOXO3a transduction activated the atrogin-1 promoter in both cultured myocytes and mouse heart. Thus, in cardiomyocytes, as in skeletal muscle, FOXO3a activates an atrogene transcriptional program, which retards or prevents hypertrophy and is down-regulated by multiple physiological and pathological stimuli of myocyte growth.

Angiotensin II↗
PubMed2005

Metabolic energetics and genetics in the heart.

From the first stages of differentiation in the embryo to the end of life, energy substrate metabolism and function are inextricably linked features of the heart. The principle of energy substrate metabolism is simple. For a given developmental stage and for a given environment, the heart oxidizes the most efficient fuel on the path to ATP. The "multitasking" of energy substrate metabolism in the heart entails more than the generation of reducing equivalents for oxidative phosphorylation of ADP in the respiratory chain. In the postnatal heart, substrate switching and metabolic flexibility are features of normal function. In the stressed heart, metabolic remodeling precedes, triggers, and sustains functional and structural remodeling. This manuscript reviews the pleiotropic actions of metabolism in energy transfer, signal transduction, cardiac growth, gene expression, and viability. Examples are presented to illustrate that metabolic signals of stressed and failing heart are the product of complex cellular processes. An early feature of the maladapted heart is a loss of metabolic flexibility. The example of lipotoxic heart failure illustrates the concept of sustained metabolic dysregulation as a cause of contractile dysfunction of the heart. Thus, a paradigm emerges in which metabolic signals not only regulate fluxes through enzyme catalyzed reactions in existing metabolic pathways, but also regulate transcriptional, translational, and post-translational signaling in the heart. As new insights are gained into metabolic adaptation and maladaptation of the heart, metabolic modulation may become an effective strategy for the treatment of heart failure.

Animals↗
PubMed2004

PPAR-gamma agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation.

Previously we reported that the beneficial effects of beta-adrenergic blockade in chronic mitral regurgitation (MR) were in part due to induction of bradycardia, which obviously affects myocardial energy requirements. From this observation we hypothesized that part of the pathophysiology of MR may involve faulty energy substrate utilization, which in turn might lead to potentially harmful lipid accumulation as observed in other models of heart failure. To explore this hypothesis, we measured triglyceride accumulation in the myocardia of dogs with chronic MR and then attempted to enhance myocardial metabolism by chronic administration of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone. Cardiac tissues were obtained from three groups of dogs that included control animals, dogs with MR for 3 mo without treatment, and dogs with MR for 6 mo that were treated with rosiglitazone (8 mg/day) for the last 3 mo of observation. Hemodynamics and contractile function (end-systolic stress-strain relationship, as measured by K index) were assessed at baseline, 3 mo of MR, and 6 mo of MR (3 mo of the treatment). Lipid accumulation in MR (as indicated by oil red O staining score and TLC analysis) was marked and showed an inverse correlation with the left ventricular (LV) contractility. LV contractility was significantly restored after PPAR therapy (K index: therapy, 3.01 +/- 0.11*; 3 mo MR, 2.12 +/- 0.34; baseline, 4.01 +/- 0.29; ANOVA, P = 0.038; *P < 0.05 vs. 3 mo of MR). At the same time, therapy resulted in a marked reduction of intramyocyte lipid. We conclude that 1) chronic MR leads to intramyocyte myocardial lipid accumulation and contractile dysfunction, and 2) administration of the PPAR-gamma agonist rosiglitazone ameliorates MR-induced LV dysfunction accompanied by a decline in lipid content.

Animals↗
PubMed2004

Hypoxia-induced decrease of UCP3 gene expression in rat heart parallels metabolic gene switching but fails to affect mitochondrial respiratory coupling.

Mitochondrial uncoupling proteins 2 and 3 (UCP2 and UCP3) are postulated to contribute to antioxidant defense, nutrient partitioning, and energy efficiency in the heart. To distinguish isotype function in response to metabolic stress we measured cardiac mitochondrial function and cardiac UCP gene expression following chronic hypobaric hypoxia. Isolated mitochondrial O(2) consumption and ATP synthesis rate were reduced but respiratory coupling was unchanged compared to normoxic groups. Concurrently, left ventricular UCP3 mRNA levels were significantly decreased with hypoxia (p<0.05) while UCP2 levels remained unchanged versus controls. Diminished UCP3 expression was associated with coordinate regulation of counter-regulatory metabolic genes. From these data, we propose a role for UCP3 in the regulation of fatty acid oxidation in the heart as opposed to uncoupling of mitochondria. Moreover, the divergent hypoxia-induced regulation of UCP2 and UCP3 supports distinct mitochondrial regulatory functions of these inner mitochondrial membrane proteins in the heart in response to metabolic stress.

Animals↗
PubMed2004

Degree of cardiac fibrosis and hypertrophy at time of implantation predicts myocardial improvement during left ventricular assist device support.

BACKGROUND: There have been increasing reports of cardiac improvement in heart failure patients supported by left ventricular assist devices (LVADs i.e.), including a number of patients who have tolerated removal of the device without the benefit of cardiac transplant. In the current study, we retrospectively investigated echocardiographic and histologic changes in patients supported by LVADs (n = 18). The goal of our study was to determine if the degree of cardiac fibrosis and myocyte size in pre-implant biopsies could predict myocardial improvement as assessed by improvements in ejection fraction (EF) during LVAD support. METHODS: We determined total collagen content in myocardial biopsy specimens by a semi-quantitative analysis of positive Picro-Sirius Red-stained areas and myocyte size measurements by computerized edge detection software. RESULTS: During LVAD support, 9 of the 18 patients (Group A) were distinguished by significant improvement in ejection fraction (pre <20% vs unloaded 34 +/- 5%). In addition, Group A patients had significantly less fibrosis and smaller myocytes than their Group B counterparts, whose EF did not improve. There was an inverse correlation between pre-implant biopsy collagen levels and myocyte size with increases in EF during LVAD unloading. CONCLUSIONS: We found that the patients who demonstrated the greatest improvements in EF during support had less fibrosis and smaller myocytes at the time of device implantation. We propose that tissue profiling a patient's pre-implant biopsy for fibrosis and myocyte size may allow stratification in Stage IV heart failure and may predict myocardial improvement during LVAD support.

Adolescent↗
PubMed2004

Linking gene expression to function: metabolic flexibility in the normal and diseased heart.

Metabolism transfers energy from substrates to ATP. As a "metabolic omnivore," the normal heart adapts to changes in the environment by switching from one substrate to another. We propose that this flexibility is lost in the maladapted, diseased heart. Both adaptation and maladaptation are the results of metabolic signals that regulate transcription of key cardiac regulatory genes. We propose that metabolic remodeling precedes, initiates, and sustains functional and structural remodeling. The process of metabolic remodeling then becomes a target for pharmacological intervention restoring metabolic flexibility and normal contractile function of the heart.

Diabetes Mellitus↗
PubMed2003

Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy.

Hypobaric hypoxia induces right ventricular hypertrophy. The relative contribution of pulmonary hypertension, decreased arterial oxygen, and neuroendocrine stimulation to the transcriptional profile of hypoxia-induced right ventricular hypertrophy is unknown. Whereas both ventricles are exposed to hypoxia and neuroendocrine stimulation, only the right ventricle is exposed to increased load. We postulated that right ventricular hypertrophy would reactivate the fetal gene transcriptional profile in response to increased load. We measured the expression of candidate genes in the right ventricle of rats exposed to hypobaric hypoxia (11% O(2)) and compared the results with the left ventricle. Hypoxia induced right ventricular hypertrophy without fibrosis. In the right ventricle only, atrial natriuretic factor transcript levels progressively increased starting at day 7. Metabolic genes were differentially regulated, suggesting a substrate switch from fatty acids to glucose during early hypoxia and a switch back to fatty acids by day 14. There was also a switch in myosin isogene expression and a downregulation of sarcoplasmic/endoplasmic ATPase 2a during early hypoxia, whereas later, both myosin isoforms and SERCA2a were upregulated. When the right and left ventricle were compared, the transcript levels of all genes, except for myosin isoforms and pyruvate dehydrogenase kinase-4, differed dramatically suggesting that all these genes are regulated by load. Our findings demonstrate that hypoxia-induced right ventricular hypertrophy transiently reactivates the fetal gene program. Furthermore, myosin iso-gene and pyruvate dehydrogenase kinase-4 expression is not affected by load, suggesting that either hypoxia itself or neuroendocrine stimulation is the primary regulator of these genes.

Adaptation, Physiological↗
PubMed2003

Atrophic remodeling of the heart in vivo simultaneously activates pathways of protein synthesis and degradation.

BACKGROUND: Mechanical unloading of the heart results in atrophic remodeling. In skeletal muscle, atrophy is associated with inactivation of the mammalian target of rapamycin (mTOR) pathway and upregulation of critical components of the ubiquitin proteosome proteolytic (UPP) pathway. The hypothesis is that mechanical unloading of the mammalian heart has differential effects on pathways of protein synthesis and degradation. METHODS AND RESULTS: In a model of atrophic remodeling induced by heterotopic transplantation of the rat heart, we measured gene transcription, protein expression, polyubiquitin content, and regulators of the mTOR pathway at 2, 4, 7, and 28 days. In atrophic hearts, there was an increase in polyubiquitin content that peaked at 7 days and decreased by 28 days. Furthermore, gene and protein expression of UbcH2, a ubiquitin conjugating enzyme, was also increased early in the course of unloading. Transcript levels of TNF-alpha, a known regulator of UbcH2-dependent ubiquitin conjugating activity, were upregulated early and transiently in the atrophying rat heart. Unexpectedly, p70S6K and 4EBP1, downstream components of mTOR, were activated in atrophic rat heart. This activation was independent of Akt, a known upstream regulator of mTOR. Rapamycin treatment of the unloaded rat hearts inhibited the activation of p70S6K and 4EBP1 and subsequently augmented atrophy in these hearts compared with vehicle-treated, unloaded hearts. CONCLUSIONS: Atrophy of the heart, secondary to mechanical unloading, is associated with early activation of the UPP. The simultaneous activation of the mTOR pathway suggests active remodeling, involving both protein synthesis and degradation.

Animals↗
PubMed2003

Hypoxia-induced switches of myosin heavy chain iso-gene expression in rat heart.

Cardiac hypertrophy and atrophy increase expression of fetal iso-genes. A common factor is a decrease in cellular oxygen tension. To test the hypothesis that hypoxia changes cardiac MHC iso-gene expression Wistar rats were exposed to 24 and 48 h of hypobaric hypoxia (11% oxygen) and mRNA was isolated from the left ventricle. In addition, neonatal rat cardiomyocytes were incubated for up to 48 h in a hypoxic chamber. Transcript levels of MHCalpha (adult isoform), MHCbeta (fetal isoform), and Nkx2.5, the earliest known marker for cardiogenesis, were measured by real-time quantitative RT-PCR and normalized to levels of 18S rRNA. Expression of the transcription factor Nkx2.5 increased with hypoxia. Hypoxia decreased MHCalpha and increased MHCbeta transcript levels, both in vivo and in vitro. We conclude that hypoxia per se induces a pattern of isoform gene expression associated with early cardiac development.

Animals↗