Showing papers by "Angelino Calderone published in 2007"

Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: A novel consideration in atrial remodeling

Abstract: Objective Atrial fibrillation (AF) causes tachycardia-induced atrial electrical remodeling, contributing to the progressive nature of the arrhythmia. Ventricular dysfunction due to a rapid response to AF can cause structural remodeling, but whether AF itself directly promotes atrial fibrosis is controversial. This study investigated the hypothesis that rapid atrial cardiomyocyte activation produces factors that influence atrial fibroblast proliferation and secretory functions. Methods Cultured canine atrial fibroblasts were treated with medium from rapidly-paced atrial cardiomyocytes, non-paced cardiomyocytes and cardiomyocyte-pacing medium only, and analyzed by [3H]thymidine incorporation, Western blot and real-time RT-PCR. Results Rapidly-paced cardiomyocyte-conditioned medium reduced [3H]thymidine uptake compared to non-paced cardiomyocyte-conditioned medium and medium alone (∼85%, P <0.01). Rapidly-paced cardiomyocyte medium increased αSMA protein (∼55%, p <0.001), collagen-1 (∼85%, P <0.05) and fibronectin-1 (∼205%, P <0.05) mRNA expression vs. controls. The angiotensin-1 receptor blocker valsartan attenuated pacing-induced αSMA changes but did not affect fibroblast proliferation. Suppression of contraction with blebbistatin did not prevent tachypacing-induced changes in [3H]thymidine uptake or αSMA upregulation, pointing to a primary role of electrical over mechanical cardiomyocyte activity. Atrial tissue from 1-week atrial-tachypaced dogs with ventricular rate control similarly showed upregulation of αSMA protein (∼40%, P <0.05), collagen-1 (∼380%, P <0.01) and fibronectin-1 (∼430%, P <0.001) mRNA versus shams. Conclusions Rapidly-paced cardiomyocytes release substances that profoundly alter cardiac fibroblast function, inducing an activated myofibroblast phenotype that is reflected by increased ECM-gene expression in vivo . These findings are consistent with recent observations that AF per se may cause ECM remodeling, and have potentially important consequences for understanding and preventing the mechanisms underlying AF progression.

Effects of resveratrol (trans-3,5,4'-trihydroxystilbene) treatment on cardiac remodeling following myocardial infarction.

Abstract: Resveratrol (RES; trans -3,5,4′-trihydroxystilbene) has been shown to improve health and slow the progression of disease in various models. Several cardioprotective mechanisms have been identified including antioxidant, anti-inflammatory, and antifibrotic actions. Each of these actions is thought to have the ability to attenuate the pathophysiology underlying the deleterious cardiac structural remodeling that results from acute myocardial infarction (MI). Therefore, we evaluated the effect of resveratrol treatment on the progression of cardiac remodeling after MI. Four groups of rats (sham, n = 6; sham + RES, n = 21; MI, n = 26; MI + RES, n = 24) were treated for 13 weeks, starting 7 days before ligation of the left anterior descending coronary artery. Serial transthoracic echocardiography revealed that resveratrol had no effect on MI-induced left-ventricular and left-atrial dilatation or reduction in left-ventricular fractional shortening. Consistent with these findings, resveratrol did not improve the deterioration of hemodynamic function or reduce infarct size at 12 weeks post-MI. Resveratrol-treated animals did, however, show preserved cardiac contractile reserve in response to dobutamine administration. Radioligand binding revealed that MI reduced β-adrenergic receptor density. Resveratrol administration increased β-adrenoceptor density, so that resveratrol-treated MI rats had β-adrenoceptor densities similar to normal rats. Real-time reverse transcription-polymerase chain reaction revealed that MI-induced changes in sarcoplasmic reticulum Ca 2+ -ATPase 2 and transforming growth factor β-1 expression were unaltered by resveratrol, whereas MI-induced increases in atrial natriuretic factor (ANF) and connective tissue growth factor (CTGF) expression were attenuated. Resveratrol treatment does not improve cardiac remodeling and global hemodynamic function post-MI but does preserve contractile reserve and attenuate ANF and CTGF up-regulation.

Antagonism of stromal cell-derived factor-1α reduces infarct size and improves ventricular function after myocardial infarction

Abstract: To examine the biological impact of locally expressed stromal cell-derived factor-1α (SDF-1α) during the acute phase of remodeling after myocardial infarction (MI), rats were treated with the selective CXCR4 receptor antagonist AMD3100 (1 mg/kg; given 24 h post-MI and continued for 6 days). In 1-week post-MI rats, intense SDF-1 immunoreactivity was detected in scar-residing vessels, and SDF-1α messenger ribonucleic acid (mRNA) levels were significantly greater in the infarct region compared to the noninfarcted left ventricle (NILV). AMD3100 treatment of post-MI rats reduced infarct size, improved systolic function, and partially suppressed the increased expression of atrial natriuretic peptide mRNA in the NILV. The latter finding indirectly suggests that SDF-1α may have contributed to the hypertrophic response of the NILV. SDF-1α treatment of neonatal rat ventricular myocytes (NNVMs) failed to promote protein synthesis. However, in hypertrophied NNVMs, SDF-1α treatment further augmented 3H-leucine uptake, and AMD3100 selectively inhibited the increase in protein synthesis. Collectively, these data support the existence of an SDF-1α gradient in the damaged rat myocardium increasing toward the infarct region and highlight the novel observation that AMD3100 antagonism of the SDF-1α/CXCR4 axis reduced scar expansion and improved contractility. In vitro data further suggest that SDF-1α may have contributed to the hypertrophic response of the NILV.

Tamoxifen treatment of myocardial infarcted female rats exacerbates scar formation

Abstract: Hormonal replacement therapy in postmenopausal women was associated with an increased incidence of nonfatal myocardial infarction. Selective estrogen receptor modulators were considered an alternative pharmacological approach. However, selective estrogen receptor modulators acting via estrogen receptor-dependent and receptor-independent mechanisms may negatively influence cardiac remodeling. The present study tested the hypothesis that tamoxifen (TAM) treatment after coronary artery ligation compromised scar formation. TAM administration (10 mg kg(-1) day(-1) for 3 weeks) to postmyocardial infarcted (MI) female adult rats significantly increased scar surface area (TAM+MI = 0.67 +/- 0.08 vs MI = 0.45 +/- 0.06 cm(2)) and weight (TAM+MI = 0.071 +/- 0.007 vs MI = 0.050 +/- 0.006 grams). In the infarct region, a significant decrease (p < 0.05) of small calibre vessels (lumen diameter <50 microm) was observed in TAM treated post-MI rats (4.5 +/- 0.8 vessels/mm(2)), as compared to untreated MI rats (7 +/- 0.7 vessels/mm(2)). Consistent with the latter finding, 4-OH TAM caused a dose-dependent suppression of vascular endothelial growth factor (VEGF)-stimulated (10(-9) mol/l) capillarity-like tubule formation by rat aortic endothelial cells in vitro via an estrogen receptor-independent mechanism. These data have demonstrated that TAM treatment of post-MI female rats exacerbated scar formation and may have occurred at least in part via the attenuation of new vessel formation in the infarct region.

Rapid electrical pacing of cardiomyocytes alters the behavior of cardiac fibroblasts: Implications for atrial fibrillations

Abstract: Background: Atrial fibrillation (AF) produces atrial tachycardia-related changes in atrial electrophysiology, providing a possible explanation for the progressive nature of the arrhythmia Structural remodeling results from ventricular dysfunction due to a rapid response to AF, but whether AF itself can cause atrial fibrosis remains unclear This study investigated the hypothesis that rapid atrial cardiomyocyte activation produces factors that influence atrial fibroblast proliferation and secretory functions Methods: Cultured canine atrial fibroblasts were treated with medium from rapidly-paced atrial cardiomyocytes (group 5Hz), non-paced cardiomyocytes (group NP) and cardiomyocyte pacing medium alone (group O), and analyzed by [3H]thymidine incorporation, Western-blot and real-time RT-PCR Results: Rapidly-paced cardiomyocyte-conditioned medium had a potent anti-proliferative effect, reducing [3H]thymidine uptake compared to non-paced cardiomyocyte-conditioned medium and medium alone (2,143±1,490** vs 15,870±3,343 and 16,440±4,193 respectively, **P < 001 vs both NP and O) Conditioned medium from rapidly-paced cardiomyocytes increased αSMA protein reflecting an activated myofibroblast phenotype (162±020** vs 108±026 and 101±024), collagen-1 (241±022* vs 149±033 and 110±019, *P < 005 both NP and O) and fibronectin-1 (305±028* vs 180±045 and 120±019) mRNA expression compared to control cells Treatment of the conditioned medium with the AT1 receptor blocker valsartan, partially attenuated the pacing-induced αSMA increase but had no effect on fibroblast proliferation Atrial tissue from 1-week atrial-tachypaced dogs with AV block/ventricular pacing to control ventricular rate similarly showed upregulation of collagen-1 (26±05 vs 07±03, P < 001) and fibronectin-1 (49±06 vs 11±04, P < 0001) mRNA versus unpaced shams Conclusion: Rapidly-paced cardiomyocytes release substances that profoundly alter cardiac fibroblast function and induce an activated myofibroblast phenotype that is reflected by altered ECM-gene expression in vivo These findings are consistent with recent observations that AF per se causes ECM remodeling and may have important consequences for understanding and preventing the mechanisms underlying AF progression