Biomedical subjects

Jacob Joseph

Publications and source records attributed to Jacob Joseph.

At least 19 recordsLinked to original sources

PubMed2026

Multi-ancestry genetic architecture of heart failure subtypes.

Heart failure (HF) affects 6.7 million people in the US and includes two major subtypes, HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), with distinct genetic architectures. We meta-analyze genome-wide association studies (GWAS) of 38,781 HFrEF cases, 38,163 HFpEF cases, and 526,135 controls across European, African, Hispanic, and Asian ancestries using the Million Veteran Program and Vanderbilt University DNA Databank (BioVU). We identify 46 genome-wide significant loci for HFrEF (9 novel) and 3 loci for HFpEF (1 novel). Four HFrEF loci are detected in African ancestry participants near CD36, SPI1, TRIM48, and SPNS3, with lead SNPs showing low risk-allele frequencies in European populations. In the all-cause HF meta-analysis (200,070 cases, 2,076,466 controls), we identify 136 loci (12 novel). Gene-based tests, tissue enrichment, transcriptome-wide association, and fine-mapping implicate vascular, metabolic, and TGF-β/Smad signaling pathways and nominate candidate causal genes, clarifying shared and subtype-specific risk across ancestries.

Humans↗

PubMed2006

Safety and effectiveness of granulocyte-colony stimulating factor in mobilizing stem cells and improving cytokine profile in advanced chronic heart failure.

The objective of this study was to determine a safe and effective dose of granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells in patients with advanced heart failure and to determine its effects on the cytokine profile. Patients with advanced heart failure (n = 6) and implantable defibrillators in situ were administered G-CSF after baseline echocardiographic and laboratory evaluation, using an escalating dose schedule designed to ensure safety. The peripheral CD34+ hematopoietic stem cell count increased from 3.6 +/- 0.5/microl to 38.7 +/- 13/microl (p= 0.022) after 5 days of 5 microg/kg/day G-CSF therapy. The baseline or peak white blood cell count did not predict the stem cell response. G-CSF increased plasma levels of interleukin-10. Left ventricular ejection fraction increased significantly in the 4 patients with ischemic cardiomyopathy 9 months after treatment. No major adverse effects attributable to the drug occurred during administration or 9 months of follow-up. Our results have shown that low-dose G-CSF significantly mobilized hematopoietic stem cells in advanced heart failure and improved left ventricular function in the ischemic subset of patients. G-CSF significantly increased plasma levels of the anti-inflammatory cytokine interleukin-10, without changing pro-inflammatory cytokine levels. In conclusion, these results indicate a novel mechanism of action for the potential therapeutic benefit of G-CSF in advanced ischemic cardiomyopathy.

Aged↗

PubMed2006

Cardiovascular effects of hyperhomocysteinemia in conscious unrestrained rats.

BACKGROUND: Experiments were designed to determine whether hyperhomocysteinemia (Hhe) affects cardiovascular function when monitored in conscious unrestrained animals. METHODS: Adult, male Sprague-Dawley rats were fed a homocystine-supplemented diet for 6 months. Blood pressure (BP), heart rate, and pulse pressure were monitored continuously, 24 h a day, using biotelemetry techniques. RESULTS: The resulting intermediate level of Hhe was not associated with significant changes in heart rate, diastolic BP, systolic BP, or the circadian variation in heart rate. In spite of the lack of significant changes in systolic and diastolic BP, there was a slight but statistically significant increase in pulse pressure after 4 months of treatment that returned toward control levels after 6 months. CONCLUSIONS: Current results indicate that Hhe alone does not have significant effects on BP. Furthermore, they suggest that the previously reported Hhe-induced adverse cardiac remodeling and diastolic dysfunction in this animal model are not the result of pressure overload.

Animals↗

PubMed2006

Cardiac nonamyloidotic immunoglobulin deposition disease.

Cardiac nonamyloidotic immunoglobulin (Ig) deposition disease (CIDD) is a rare disorder characterized by Ig deposition in the myocardium associated with plasma cell dyscrasias. A retrospective review of cardiac biopsies performed at two different institutions identified eight patients with CIDD. All patients had plasma cell dyscrasias with monoclonal gammopathy. Three had IgG lambda, two had IgG kappa, one had IgD kappa and one each had free kappa and free lambda light chain. Four patients had concurrent amyloidosis involving other organs. One had amyloidosis of kidney alone, one had amyloidosis of kidney and abdominal fat pad and two others had amyloidosis of bone marrow vasculature. Three patients had dialysis-dependent renal insufficiency. None of the patients had symptoms of heart failure. Six patients had echocardiographically demonstrable concentric left ventricular hypertrophy with diastolic dysfunction. Two patients had significant cardiac arrhythmias requiring medical intervention. On endomyocardial biopsy, all eight had normal appearing myocardium on light microscopy with negative Congo Red and Thioflavin T stains. On immunofluorescent staining of the cardiac biopsies, all eight stained positive for interstitial Ig deposition. Electron microscopy (EM) confirmed the presence of granular deposits of Igs in the myocardium in five of the eight patients. EM studies were not available in one patient and two others had normal EM studies. In conclusion, CIDD should be considered in the spectrum of cardiovascular pathology in patients with plasma cell dyscrasias. They often, but not always, have left ventricular hypertrophy. These patients may be at risk for developing arrhythmias as well as diastolic dysfunction. Unless immunofluorescent and EM studies are performed routinely in biopsy material, this entity may be missed in the absence of amyloidosis. Concurrent amyloidosis in other organs sheds a unique perspective into the role of local microenvironment in the pathogenesis of systemic Ig deposition disease and amyloidosis.

Adult↗

PubMed2006

Acute dilatory and negative inotropic effects of homocysteine are inhibited by an adenosine blocker.

1. Previous studies have shown that homocysteine elicits acute negative inotropic and coronary vasodilatory effects in rat hearts. In addition, this earlier work suggested that the inotropic action is mediated via an endothelium-derived agent that is neither nitric oxide (NO) nor a cyclooxygenase product, while the coronary actions were found to be antagonized by the NOS inhibitor l-NNA. Current experiments, which utilized coronary-perfused rat hearts, were designed to determine if muscarinic or adenosine receptors are involved in these acute actions of homocysteine. 2. Left ventricular developed pressure was used as a measure of systolic function in electrically paced, Langendorff-perfused heart with coronary pressure being used to monitor coronary vascular tone. Acute effects of homocysteine (10-300 micromol/L) were examined in the presence and absence of 1 yen 10(-6) mol atropine or 7 yen 10(-5) mol 8-(p-sulfophenyl) theophylline (SPT), a non-selective adenosine receptor antagonist. 3. Atropine had no effect on either the inotropic or vascular actions of homocysteine. In contrast, SPT partially antagonized both actions of the amino acid with the antagonism of the vasodilation being much greater than its inhibition of the negative inotropic effect. Experiments with adenosine demonstrated that the selected dose of SPT elicited marked rightward shifts in the dose-response curves for both the inotropic and vascular actions. 4. Current results suggest that adenosine plays a role in both the negative inotropic and vasodilatory actions of homocysteine. However, the relatively minor antagonistic action of SPT on the inotropic effect of homocysteine suggests that additional endothelium-derived mediators underlie its effects on contractility.

Acetylcholine↗

PubMed2005

Influence of mast cells on structural and functional manifestations of radiation-induced heart disease.

Radiation-induced heart disease (RIHD), characterized by accelerated atherosclerosis and adverse tissue remodeling, is a serious sequelae after radiotherapy of thoracic and chest wall tumors. Adverse cardiac remodeling in RIHD and other cardiac disorders is frequently accompanied by mast cell hyperplasia, suggesting that mast cells may affect the development of cardiac fibrosis. This study used a mast cell-deficient rat model to define the role of mast cells in RIHD. Mast cell-deficient rats (Ws/Ws) and mast cell-competent littermate controls (+/+) were exposed to 18 Gy localized single-dose irradiation of the heart. Six months after irradiation, cardiac function was examined by echocardiography and Langendorff-perfused isolated heart preparation, whereas structural changes were assessed using quantitative histology and immunohistochemical analysis. Mast cell-deficient rats exhibited more severe postradiation changes than mast cell-competent littermates. Hence, mast cell-deficient rats exhibited a greater upward/leftward shift in the left ventricular (LV) diastolic pressure-volume relationship (P = 0.001), a greater reduction in in vivo LV diastolic area (from 0.50 +/- 0.024 cm in age-matched controls to 0.24 +/- 0.032 cm after irradiation; P = 0.006), and a greater increase in LV posterior wall thickness (from 0.13 +/- 0.003 cm in age-matched controls to 0.15 +/- 0.003 cm after irradiation; P = 0.04). Structural analysis revealed more pronounced postradiation accumulation of interstitial collagen III but less myocardial degeneration in hearts from mast cell-deficient rats. These data show that the absence of mast cells accelerates the development of functional changes in the irradiated heart, particularly diastolic dysfunction, and suggest that, in contrast to what has been the prevailing assumption, the role of mast cells in RIHD is predominantly protective.

Animals↗

PubMed2005

Trends in the care of patients with acute myocardial infarction at a university-affiliated Veterans Affairs Medical Center.

BACKGROUND: Acute cardiac care of the veterans at Veterans Administration (VA) hospitals has been thought of as poor in quality. We examined the use of life-saving, evidence-based medical therapy in patients admitted with acute myocardial infarction to the University of Arkansas for Medical Sciences-affiliated VA Medical Center in Little Rock and compared the use of this therapy with other hospitals in Arkansas and in the rest of the nation. METHODS: Use of life-saving medical therapy in 117 patients admitted with acute myocardial infarction from January 2002 to December 2002 was compared with the National Registry of Myocardial Infarction database for the identical period. RESULTS: Heparin/low-molecular-weight heparin and glycoprotein IIb/IIIa inhibitors were used in 88% and 66% of patients, respectively. Aspirin, beta adrenergic-blocking agents, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) were used in 92%, 93%, 62%, and 79% of the patients, respectively. The use of these therapies was better than in similar patients in Arkansas (P < .001) and the United States as a whole (P < .01). Calcium-channel blockers were used in 16% of the patients. At a mean follow-up period of 1.5 years, use of beta blockers and aspirin had decreased, whereas the use of statins and ACE inhibitors/ARBs was unchanged. CONCLUSION: This study shows that patients with acute myocardial infarction admitted to this university-affiliated VA Medical Center receive evidence-based life-saving medical therapy more often than in the rest Arkansas or in the entire United States. More important, patients at this federal institution continue to receive life-saving medical therapy during follow-up. Better use of evidence-based therapy may be related to affiliation of this VA Medical Center with a teaching institution where board certified cardiologists are involved in short- and long-term care of these patients.

Adrenergic beta-Antagonists↗

PubMed2004

Protective role of mast cells in homocysteine-induced cardiac remodeling.

Recent reports including those from our laboratories indicate that hyperhomocysteinemia (Hhe) is an independent risk factor for cardiac dysfunction and clinical heart failure. Mast cell accumulation is a prominent feature in our model of Hhe-induced cardiac dysfunction. Because mast cell-derived mediators can potentially attenuate cardiac remodeling, we investigated the possible protective role of mast cells in Hhe-induced cardiac remodeling using a mast cell-deficient rat model that in our recent report did not demonstrate any adverse cardiac function at younger age (6 mo) than mast cell-competent control animals. Mast cell-deficient (Ws/Ws) rats and mast cell-competent (+/+) littermate control animals (3 mo of age) were treated with a Hhe-inducing diet for 10 wk. Cardiac remodeling was assessed structurally utilizing histomorphometric methods and functionally using an isolated Langendorff-perfused heart preparation. The Hhe-inducing diet caused similar elevations of homocysteine levels in the two groups. Compared with Hhe +/+ rats, the Hhe Ws/Ws rats demonstrated strikingly exacerbated adverse cardiac remodeling and myocardial fibrosis. Cardiac function measurement showed worsened diastolic function in Hhe Ws/Ws rats compared with Hhe +/+ rats. The absence of mast cells strikingly exacerbates Hhe-induced adverse cardiac remodeling and diastolic dysfunction. These findings indicate a potential dual rather than sole deleterious role for mast cells in cardiac injury.

Animals↗

PubMed2004

Transforming growth factor beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II.

Angiotensin II (Ang II) is a powerful mediator of adverse cardiac remodeling and fibrosis. However, the mechanisms of Ang II-induced myocardial fibrosis remain to be clarified. We postulated that Ang II alters transforming growth factor beta (TGF-beta) receptor expression, specifically that of endoglin, and thereby modulates cardiac fibroblast (CF) collagen metabolism. Experiments were conducted using CF from adult Sprague Dawley rats to determine the expression of TGF-beta1 receptors including endoglin, and the role of Ang II type 1 (AT1) and type 2 (AT2) receptors, and MAPK p42/44 in this process. The functional role of endoglin in modulating Ang II effects on matrix metalloproteinase-1 (MMP-1) and type I collagen expression was also analyzed. Endoglin gene and protein expression were consistently identified in quiescent CFs. Ang II increased the expression of endoglin mRNA and protein in a concentration and time-dependent manner, with no effect on TGF-beta receptors I and II expression. This effect was AT1 receptor mediated, because AT1 receptor antagonists valsartan, candesartan, and losartan inhibited Ang II-induced endoglin expression, whereas the AT2 receptor antagonist PD123319 had no effect. MAPKp42/44 inhibition attenuated Ang II-induced endoglin expression. Ang II-induced decrease in MMP-1 protein expression and increase in type I collagen protein expression were both blocked by a specific endoglin antibody. Hence, our results indicate that endoglin is upregulated in CFs by Ang II via the AT1 receptor and modulates profibrotic effects of Ang II. These findings provide novel insights into Ang II-induced cardiac remodeling.

Angiotensin II↗

PubMed2004

Cardiac function in hearts isolated from a rat model deficient in mast cells.

Several studies have examined the role of mast cells in the myocardial response to injury such as that caused by hypertension and ischemia-reperfusion. However, little is known about the influence of mast cells on normal myocardial structure and function. The present experiments examined cardiac function in Langendorff-perfused hearts isolated from 6- and 9-mo-old male mast cell-deficient (Ws/Ws) and mast cell-competent rats. A fluid-filled balloon catheter was used to measure left ventricular diastolic and systolic function at increasing preload volumes. At 6 mo of age, mast cell-deficient rats showed a slight cardiac hypertrophy (as monitored by heart weight and heart weight-to-body weight ratio) but no significant change in maximum observed systolic or diastolic function. In contrast, at 9 mo of age, the mast cell-deficient group showed no signs of hypertrophy but displayed a diastolic dysfunction characterized by decreased compliance without a significant decline in maximum observed basal -dP/dtmax. There were no significant differences in maximum observed values for measures of systolic function (developed pressure and +dP/dtmax). In summary, the results of this study in adult rats suggest that mast cells influence cardiac function in the absence of injury and that observed differences between mast cell-competent and -deficient animals vary with age. Thus it is important to consider these "physiological" actions and resulting changes in function when studying effects of insult in mast cell-deficient models.

Animals↗

PubMed2004

Acute negative inotropic effects of homocysteine are mediated via the endothelium.

Previous studies have shown that chronic hyperhomocysteinemia is associated with an adverse cardiac remodeling and heart failure. This study, which utilized coronary-perfused hearts and superfused papillary muscle, was designed to determine whether homocysteine acts acutely to alter cardiac contractile function. Left ventricular developed pressure was used as a measure of systolic function in the Langendorff-perfused heart, whereas isometric developed tension was used in papillary muscle. All preparations were bathed in physiological buffer and paced electrically. Initial results showed that homocysteine elicits a relatively rapid onset (maximum effect observed within 5 min), concentration-dependent (10-300 microM), and moderate negative inotropic action (maximum decrease in tension was approximately 15% of control values) in Langendorff-perfused hearts but not in papillary muscle. In contrast, effluent from homocysteine-treated hearts decreased contractility in papillary muscle, and all inotropic actions were largely eliminated when brief Triton X-100 treatment was utilized to inactivate the coronary endothelium in the intact heart. The homocysteine-induced decrease in contractile function was not antagonized by N(omega)-nitro-l-arginine, a nitric oxide synthase inhibitor, or the cyclooxygenase inhibitor indomethacin. Thus data suggest that pathophysiological concentrations of homocysteine elicit an acute negative inotropic effect on ventricular myocardium that is mediated by a coronary endothelium-derived agent other than nitric oxide or products of cyclooxygenase. Future studies are required to elucidate the mechanism by which homocysteine acts to elicit the release of the proposed endothelial mediator, the identity of the proposed paracrine agent, and the mechanism of its negative inotropic action.

Animals↗

PubMed2003

Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats.

A recent report indicated that hyperhomocysteinemia (Hhe), in addition to its atherothrombotic effects, exacerbates the adverse cardiac remodeling seen in response to hypertension, a powerful stimulus for pathological ventricular hypertrophy. The present study was undertaken to determine whether Hhe has a direct effect on ventricular remodeling and function in the absence of other hypertrophic stimuli. Male Wistar-Kyoto rats were fed either an amino acid-defined control diet or an intermediate Hhe-inducing diet. After 10 wk of dietary treatment, rats were subjected to echocardiographic assessment of left ventricular (LV) dimensions and systolic function. Subsequently, blood was collected for plasma homocysteine measurements, and the rats were killed for histomorphometric and biochemical assessment of cardiac remodeling and for in vitro cardiac function studies. Significant LV hypertrophy was detected by echocardiographic measurements, and in vitro results showed hypertrophy with significantly increased myocyte size in the LV and right ventricle (RV). LV and RV remodeling was characterized by a disproportionate increase in perivascular and interstitial collagen, coronary arteriolar wall thickening, and myocardial mast cell infiltration. In vitro study of LV function demonstrated abnormal diastolic function secondary to decreased compliance because the rate of relaxation did not differ between groups. LV systolic function did not vary between groups in vitro. In summary, in the absence of other hypertrophic stimuli short-term intermediate Hhe caused pathological hypertrophy and remodeling of both ventricles with diastolic dysfunction of the LV. These results demonstrate that Hhe has direct adverse effects on cardiac structure and function, which may represent a novel direct link between Hhe and cardiovascular morbidity and mortality, independent of other risk factors.

Animals↗

PubMed2003

Aspirin inhibits human coronary artery endothelial cell proliferation by upregulation of p53.

Aspirin (acetylsalicylic acid, ASA) is effective in the primary and secondary prevention of vascular events. This effect is mediated in large part by platelet inhibition; however, non-platelet-mediated effects may also be relevant in the overall efficacy of ASA. We determined the effect of ASA on the synthesis of DNA and total proteins in cultured human coronary endothelial cells (HCAECs). Fourth generation HCAECs were cultured and treated with ASA and rate of synthesis of DNA and total proteins was determined by incorporation of [3H]thymidine and [3H]proline, respectively. ASA inhibited DNA synthesis by 50% at a concentration of 1mM and protein synthesis by 50% at a concentration of 2mM. The inhibitory effect of ASA was observed as early as 2h after treatment of HCAECs. The inhibition of DNA and protein synthesis could be reversed within 24h after removal of the drug from the culture medium. Indomethacin also inhibited DNA and protein synthesis. Western blot analysis revealed that the expression of p53 protein was increased after treatment of the cells with ASA. These observations indicate that ASA decreases endothelial cell proliferation through cell cycle arrest mediated by enhanced p53 expression. Arrest of endothelial proliferation and activation may be an important mechanism of the beneficial effect of ASA in acute coronary syndromes.

Arteries↗

PubMed2003

Beta-blockade in chronic heart failure: does it work in everyone?

Chronic heart failure continues to exact a heavy burden on society due to high morbidity and mortality, in spite of advances in management. Beta-adrenergic blockade, by the suppression of sympathetic activity, attenuates the adverse ventricular remodeling seen in heart failure, and decreases mortality and hospitalization rates. Recently reported trials, meta-analyses, and sub-analyses extend the benefit of beta-blockade to severe heart failure, women, elderly patients, and African Americans. In addition, recent data also indicate the cost-effectiveness of beta-blockade in combating this deadly disease. These data indicate the strength of evidence for the use of beta-blockade for most patients with chronic heart failure.

Adrenergic beta-Antagonists↗

PubMed2003

Statins increase thrombomodulin expression and function in human endothelial cells by a nitric oxide-dependent mechanism and counteract tumor necrosis factor alpha-induced thrombomodulin downregulation.

Expression of functionally active thrombomodulin (TM) on the luminal surface of endothelial cells is critical for vascular thromboresistance. TM maintains thrombohemorrhagic homeostasis by forming a complex with thrombin, which subsequently loses its procoagulant properties and instead activates protein C. Acquired deficiency of endothelial TM is of particular pathophysiological significance in sepsis and related disorders. We show here that two different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), atorvastatin and simvastatin, strongly increase the expression and functional activity of TM in human umbilical vein endothelial cells, human coronary artery endothelial cells, and EA.hy926 endothelial cells. The increase in endothelial TM conferred by statin was prevented by the addition of mevalonic acid, geranylgeranyl-pyrophosphate, and nitric oxide scavenger, and was mimicked by the addition of a specific inhibitor of geranylgeranyl transferase, as well as by nitric oxide donors. Moreover, statin counteracted tumor necrosis factor alpha-induced downregulation of endothelial cell TM. The increase in endothelial cell TM activity in response to statin constitutes a novel pleiotropic (non-lipid-related) effect of these commonly used compounds, and may be of clinical significance in disorders where deficient endothelial TM and protein C activation play a pathophysiological role.

Anticholesteremic Agents↗

PubMed2003

Low density lipoproteins modulate collagen metabolism in fibroblasts.

High levels of low-density lipoprotein are associated with atherosclerosis, and myocardial and arterial remodeling. We postulated that low-density lipoprotein influences collagen synthesis and degradation in fibroblasts as a potential mechanism of tissue remodeling. Incubation of cultured human skin fibroblasts with low-density lipoproteins resulted in a time-dependent and dose-dependent increase in the secretion of matrix metalloproteinase activity measured by gelatin zymography. Western blot analysis showed a concomitant increase in matrix metalloproteinase-1 protein. Northern blot analysis demonstrated an increase in collagen I messenger RNA after treatment with low-density lipoprotein. The matrix metalloproteinase-1 secretory response of fibroblasts to low-density lipoprotein was attenuated by heparin, which inhibits low-density lipoprotein uptake through the low-density lipoprotein-receptor. These observations suggest that low-density lipoprotein has a regulatory effect on collagen metabolism in fibroblasts.

Blotting, Northern↗

PubMed2002

Hyperhomocysteinemia leads to adverse cardiac remodeling in hypertensive rats.

Hyperhomocysteinemia (Hhe), linked to cardiovascular disease by epidemiological studies, may be an important factor in adverse cardiac remodeling in hypertension. Specifically, convergence of myocardial and vascular alterations promoted by Hhe and hypertension may exacerbate cardiac remodeling and myocardial dysfunction. We studied male spontaneously hypertensive rats fed one of three diets: control, intermediate Hhe inducing, or severe Hhe inducing. After 10 wk of dietary intervention, cardiac function was assessed in vitro, and cardiac and coronary arteriolar remodeling were monitored by histomorphometric, immunohistochemical, and biochemical techniques. Results showed that Hhe induced diastolic dysfunction, as characterized by the diastolic pressure-volume curve, without significant changes in baseline systolic function. Perivascular collagen levels were increased by Hhe, and there was an increase in left ventricular hydroxyproline levels. Myocyte size was not affected. Coronary arteriolar wall thickness increased with Hhe due to smooth muscle hyperplasia. Mast cells increased in parallel with Hhe and collagen accumulation. In summary, 10 wk of Hhe caused coronary arteriolar remodeling, myocardial collagen deposition, and diastolic dysfunction in hypertensive rats.

Animals↗

PubMed2002

Interaction of xenobiotics with myocardial signal transduction pathways.

Although the understanding of how toxicants alter cardiac ion-channel function has matured rapidly over the past 20-30 yr, little is known about how xenobiotics may alter the signaling pathways of cardiac myocyte growth and death. Signaling molecules and pathways responsible for the growth of cardiac myocytes include the mitogen-activated protein kinases (MAPKs), janus kinase-signal transducer and activator of transcription (JAK-STATs), nuclear receptor signaling, calcineurin, and the mobilization of free calcium. Signaling molecules and pathways responsible for programmed cardiac myocyte death include the death receptors, mitochondrial proteins, p53 tumor suppressor protein, ceramide signaling, and caspases. Overlap or "crosstalk" between the various growth and death pathways in the myocardium is evident, and these pathways likely exist in a delicate balance where, for example, slight reductions in growth signaling may favor pathways leading to cardiac myocyte apoptosis. Several classical cardiotoxicants are now known to alter signaling pathways in cardiac myocytes; however, the significance of these effects is not entirely clear. Furthermore, xenobiotics that alter the interstitium or extracellular matrix, or both, may significantly alter signaling pathways in cardiac myocytes. The goal of this review is to summarize current findings regarding the interaction of xenobiotics with myocardial signal transduction pathways in the hope of stimulating new insights and highlighting important areas for future research.

Animals↗