Decreased PGC1- α levels and increased apoptotic protein signaling are associated with the maladaptive cardiac hypertrophy in hyperthyroidism.

Hyperthyroidism can lead to the activation of proteins which are associated with inflammation, apoptosis, hypertrophy, and heart failure. This study aimed to explore the inflammatory and apoptotic proteins involved in the hyperthyroidism-induced cardiac hypertrophy establishment. Male Wistar rats were divided into control and hyperthyroid (12 mg/L L-thyroxine, in drinking water for 28 days) groups. The expression of inflammatory and apoptotic signaling proteins was quantified in the left ventricle by Western blot. Hyperthyroidism was confirmed by evaluation of T3 and T4 levels, as well as cardiac hypertrophy development. There was no change in the expression of HSP70, HIF1-α, TNF-α, MyD88, p-NFκB, NFκB, p-p38, and p38. Reduced expression of p53 and PGC1-α was associated with increased TLR4 and decreased IL-10 expression. Decreased Bcl-2 expression and increased Bax/Bcl-2 ratio were also observed. The results suggest that reduced PGC1-α and IL-10, and elevated TLR4 proteins expression could be involved with the diminished mitochondrial biogenesis and anti-inflammatory response, as well as cell death signaling, in the establishment of hyperthyroidism-induced maladaptive cardiac hypertrophy.

Bucindolol attenuates the vascular remodeling of pulmonary arteries by modulating the expression of the endothelin-1 A receptor in rats with pulmonary arterial hypertension.

The aim of this study was to investigate the role of the ß-adrenergic blocker bucindolol on endothelial dysfunction and pulmonary vascular remodeling in rats with pulmonary arterial hypertension (PAH). Male Wistar rats were divided into four groups: control, monocrotaline (MCT), control?+?bucindolol and monocrotaline?+?bucindolol (MCT?+?BCD). PAH was induced by an injection of monocrotaline (60?mg/kg i.p.). After two weeks, the animals were treated for seven days with bucindolol (2?mg/kg/day i.p.) or vehicle. Echocardiography was performed upon treatment completion to analyze pulmonary vascular resistance (PVR) and right ventricle (RV) myocardial performance index. Lungs were collected for oxidative stress and western blot analysis, and the pulmonary artery was analyzed for histological and immunohistochemical parameters. The MCT?+?BCD group showed a decrease (32%) in the protein expression of endothelin-1 type A receptor (ETAR) and in the ratio of ETA/endothelin-1 type B receptor (ETBR) (62%) as compared to the MCT group. Bucindolol treatment did not alter oxidative stress, as determined by lipid peroxidation analysis and antioxidant enzyme activities and expression, endothelial nitric oxide synthase immunocontent and decreased nitrotyrosine levels. Moreover, bucindolol improved vascular remodeling of the pulmonary artery in the MCT?+?BCD group by decreasing (21%) PVR and increasing RV workload in relation to MCT.

Secoisolariciresinol diglucoside attenuates cardiac hypertrophy and oxidative stress in monocrotaline-induced right heart dysfunction.

Pulmonary arterial hypertension (PAH) occurs when remodeling of pulmonary vessels leads to increased pulmonary vascular resistance resulting in increased pulmonary arterial pressure. Increased pulmonary arterial pressure results in right ventricle hypertrophy and eventually heart failure. Oxidative stress has been implicated in the pathogenesis of PAH and may play a role in the regulation of cellular signaling involved in cardiac response to pressure overload. Secoisolariciresinol diglucoside (SDG), a component from flaxseed, has been shown to reduce cardiac oxidative stress in various pathophysiological conditions. We investigated the potential protective effects of SDG in a monocrotaline-induced model of PAH. Five- to six-week-old male Wistar rats were given a single intraperitoneal injection of monocrotaline (60 mg/kg) and sacrificed 21 days later where heart, lung, and plasma were collected. SDG (25 mg/kg) was given via gavage as either a 21-day co-treatment or pre-treatment of 14 days before monocrotaline administration and continued for 21 days. Monocrotaline led to right ventricle hypertrophy, increased lipid peroxidation, and elevated plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST). Co-treatment with SDG did not attenuate hypertrophy or ALT and AST levels but decreased reactive oxygen species (ROS) levels and catalase and superoxide dismutase activity compared to the monocrotaline-treated group. Pre-treatment with SDG decreased right ventricle hypertrophy, ROS levels, lipid peroxidation, catalase, superoxide dismutase, and glutathione peroxidase activity and plasma levels of ALT and AST when compared to the monocrotaline group. These findings indicate that pre-treatment with SDG provided better protection than co-treatment in this model of right heart dysfunction, suggesting an important role for SDG in PAH and right ventricular remodeling.

Bucindolol improves right ventricle function in rats with pulmonary arterial hypertension through the reversal of autonomic imbalance.

Pulmonary arterial hypertension (PAH) is characterised by an elevation in afterload imposed on the right ventricle (RV), leading to hypertrophy and failure. The autonomic nervous system (ANS) plays a key role in the progression to heart failure, and the use of beta-blockers attenuates this process. The aim of this study was to verify the role of bucindolol, aß1-, ß2- and α1-blocker, on the ANS, and its association with RV function in rats with PAH. Male Wistar rats were divided into four groups: control, monocrotaline, control+bucindolol, and monocrotaline+bucindolol. PAH was induced by a single intraperitoneal injection of monocrotaline (60mg/kg). After two weeks, animals were treated for seven days with bucindolol (2mg/kg/day i.p.) or vehicle. At the end of the treatment, animals underwent echocardiographic assessment, catheterisation of the femoral artery and RV, and tissue collection for morphometric and histological evaluation. In the monocrotaline+bucindolol group, there was a decrease in mean pulmonary artery pressure (33%) and pulmonary congestion (21%), when compared to the monocrotaline. Bucindolol treatment also reduced RV pleomorphism, necrosis, fibrosis and infiltration of inflammatory cells. An improvement in RV systolic function was also observed in the monocrotaline+bucindolol group compared to the monocrotaline. In addition, bucindolol promoted a decrease in the cardiac sympathovagal balance (93%) by reducing sympathetic drive (70%) and increasing parasympathetic drive (142%). Bucindolol also reduced blood pressure variability (75%). Our results show that the beneficial effects from bucindolol treatment appeared to be a consequence of the reversal of monocrotaline-induced autonomic imbalance.

Sulforaphane effects on postinfarction cardiac remodeling in rats: modulation of redox-sensitive prosurvival and proapoptotic proteins.

This study investigated whether sulforaphane (SFN), a compound found in cruciferous vegetables, could attenuate the progression of post-myocardial infarction (MI) cardiac remodeling. Male Wistar rats (350 g) were allocated to four groups: SHAM (n=8), SHAM+SFN (n=7), MI (n=8) and MI+SFN (n=5). On the third day after surgery, cardiac function was assessed and SFN treatment (5 mg/kg/day) was started. At the end of 25 days of treatment, cardiac function was assessed and heart was collected to measure collagen content, oxidative stress and protein kinase. MI and MI+SFN groups presented cardiac dysfunction, without signs of congestion. Sulforaphane reduced fibrosis (2.1-fold) in infarcted rats, which was associated with a slight attenuation in the cardiac remodeling process. Both infarcted groups presented increases in the oxidative markers xanthine oxidase and 4-hydroxinonenal, as well as a parallel increase in the antioxidant enzymes glutathione peroxidase and superoxide dismutase. Moreover, sulforaphane stimulated the cytoprotective heme oxygenase-1 (HO-1) (38%). Oxidative markers correlated with ERK 1/2 activation. In the MI+SFN group, up-regulation of ERK 1/2 (34%) and Akt (35%), as well as down-regulation of p38 (52%), was observed. This change in the prosurvival kinase balance in the MI+SFN group was related to a down-regulation of apoptosis pathways (Bax/Bcl-2/caspase-3). Sulforaphane was unable to modulate autophagy. Taken together, sulforaphane increased HO-1, which may generate a redox environment in the cardiac tissue favorable to activation of prosurvival and deactivation of prodeath pathways. In conclusion, this natural compound contributes to attenuation of the fibrotic process, which may contribute to mitigation against the progression of cardiac remodeling postinfarction.

Sulforaphane improves oxidative status without attenuating the inflammatory response or cardiac impairment induced by ischemia-reperfusion in rats.

Sulforaphane, a natural isothiocyanate, demonstrates cardioprotection associated with its capacity to stimulate endogenous antioxidants and to inhibit inflammation. The aim of this study was to investigate whether sulforaphane is capable of attenuating oxidative stress and inflammatory responses through the TLR4/MyD88/NFκB pathway, and thereby could modulate post-ischemic ventricular function in isolated rat hearts submitted to ischemia and reperfusion. Male Wistar rats received sulforaphane (10 mg·kg(-1)·day(-1)) or vehicle i.p. for 3 days. Global ischemia was performed using isolated hearts, 24 h after the last injection, by interruption of the perfusion flow. The protocol included a 20 min pre-ischemic period followed by 20 min of ischemia and a 20 min reperfusion. Although no changes in mechanical function were observed, sulforaphane induced a significant increase in superoxide dismutase and heme oxygenase-1 expression (both 66%) and significantly reduced reactive oxygen species levels (7%). No differences were observed for catalase and glutathione peroxidase expression or their activities, nor for thioredoxin reductase, glutaredoxin reductase and glutathione-S-transferase. No differences were found in lipid peroxidation or TLR4, MyD88, and NF-κB expression. In conclusion, although sulforaphane was able to stimulate endogenous antioxidants modestly, this result did not impact inflammatory signaling or cardiac function of hearts submitted to ischemia and reperfusion.

Skeletal muscle electrical stimulation improves baroreflex sensitivity and heart rate variability in heart failure rats.

The goal of the current study was to evaluate the effects of electrical stimulation (ES) on the arterial baroreflex sensitivity (BRS) and cardiovascular autonomic control in rats with chronic heart failure (CHF). Male Wistar rats were designated to one of four groups: placebo sham (P-Sham, n=9), ES sham (ES-Sham, n=9), placebo CHF (P-CHF, n=9) or ES CHF (ES-CHF, n=9). The ES was adjusted at a low frequency (30 Hz), duration of 250 µs, with hold and rest time of 8s (4 weeks, 30 min/day, 5 times/week). It was applied on the gastrocnemius muscle with intensity to produce a visible muscle contraction. The rats assigned to the placebo groups performed the same procedures with the equipment turned off. The two-way ANOVA and the post hoc Student-Newman-Keuls tests (P<0.05) were used to data comparison. The BRS was higher in ES-Sham group compared to the P-Sham group and the ES-CHF group compared to the P-CHF group. ES was able to decrease heart rate sympatho-vagal modulation and peripheral sympathetic modulation in ES-CHF compared to P-CHF group. Interestingly, heart rate sympatho-vagal modulation was similar between ES-CHF and P-Sham groups. Thus, ES enhances heart rate parasympathetic modulation on heart failure (ES-CHF) compared to placebo (P-CHF), with consequent decrease of sympatho-vagal balance in the ES-CHF group compared to the P-CHF. The results show that a 4 week ES protocol in CHF rats enhances arterial BRS and cardiovascular autonomic control.