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Pulmonary arterial hypertension (PAH) is a progressive condition that frequently leads to right ventricular (RV) remodeling. Aldosterone promotes vascular and RV remodeling. The upregulation of steroidogenic acute regulatory protein (StAR) stimulates aldosterone synthesis. However, the expression of StAR in the myocardium under PAH conditions remains unknown. To investigate the expression of StAR in the myocardium and its association with RV remodeling in PAH, utilizing spironolactone as a treatment. A PAH model was created using male Sprague-Dawley rats, which received a subcutaneous injection of Sugen5416 (20 mg/kg) and were exposed to hypoxia (10% O 2 ) for 2 weeks, followed by 2 weeks of normoxia. The animals were then divided into two groups, with one group receiving spironolactone (25 mg/kg/day) for an additional 4 weeks, while the other group did not. H9c2 cells were cultured under hypoxic conditions (37 °C, 1% O 2 , 5% CO 2 ) with or without spironolactone treatment. In the model rats, RV systolic pressure and the Fulton index, both of which increased upon exposure to Sugen5416 and hypoxia, significantly decreased with spironolactone treatment. In H9c2 cells, hypoxic exposure elevated aldosterone levels, while spironolactone treatment significantly suppressed aldosterone production. Suppression of StAR expression in the myocardium via spironolactone contributes to the improvement of RV remodeling in PAH. Spironolactone may offer a valuable therapeutic strategy for RV remodeling in patients with PAH., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O 2 ), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (12 mg/kg/d) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37 °C, 1% O 2 , 5% CO 2 ) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-κB activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.

Type 2 diabetes mellitus (T 2 DM) has been reported to be associated with cardiac remodeling. Although O-GlcNAcylation is known to be elevated in diabetic and ischemic hearts, the effects of O-GlcNAcylation on cardiac remodeling induced by intermittent hypoxia (IH), such as sleep apnea syndrome (SAS), remain unknown. To evaluate the effects, we induced IH in wild-type (WT) and transgenic O-GlcNAc transferase (Ogt-Tg) mice. Two weeks of IH increased O-GlcNAcylation in the heart tissues of both strains of mice, whereas O-GlcNAcylation in Ogt-Tg mice was significantly higher than that in WT mice under both normoxic and IH conditions. WT mice exhibited cardiac remodeling after IH, whereas cardiac remodeling was significantly attenuated in Ogt-Tg mice. Oxidative stress and apoptosis increased after IH in both strains of mice, whereas the rate of increase in these processes in Ogt-Tg mice was significantly lower than that in WT mice. To examine the mechanism of cardiac remodeling attenuation in Ogt-Tg mice after IH, the effects of O-GlcNAcylation on the activities of the master regulators nuclear factor of activated T cells (NFAT) and NF-κB were determined. The O-GlcNAcylation of GSK-3β, a negative regulator of NFAT, was significantly increased in Ogt-Tg mice, whereas the phosphorylation of GSK-3β was reciprocally reduced. The same result was observed for NF-κB p65. An in vitro reporter assay showed that the augmentation of O-GlcNAcylation by an O-GlcNAcase inhibitor suppressed NFAT and NF-κB promoter activity. These data suggest that augmented O-GlcNAcylation mitigates IH-induced cardiac remodeling by suppressing NFAT and NF-κB activities through the O-GlcNAcylation of GSK-3β and NF-κB p65.

Patients with obstructive sleep apnea (OSA) have a high prevalence of atrial fibrillation (AF). Rivaroxaban, a coagulation factor Xa inhibitor, has recently been reported to show pleiotropic effects. This study investigated the influence of rivaroxaban on cardiac remodeling caused by intermittent hypoxia (IH). Male C57BL/6J mice were exposed to IH (repeated cycles of 5% oxygen for 1.5 min followed by 21% oxygen for 5 min) for 28 days with/without rivaroxaban (12 mg/kg/day) or FSLLRY, a protease-activated receptor (PAR)-2 antagonist (10 μg/kg/day). IH caused endothelial cell degeneration in the small arteries of the right atrial myocardium and increased the level of %fibrosis and 4-hydroxy-2-nonenal protein adducts in the left ventricular myocardium. IH also increased the expression of PAR-2 as well as the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and nuclear factor-kappa B (NF-κB) were increased in human cardiac microvascular endothelial cells. However, rivaroxaban and FSLLRY significantly suppressed these changes. These findings demonstrate that rivaroxaban attenuates both atrial and ventricular remodeling induced by IH through the prevention of oxidative stress and fibrosis by suppressing the activation of ERK and NF-κB pathways via PAR-2. Treatment with rivaroxaban could potentially become a novel therapeutic strategy for cardiac remodeling in patients with OSA and AF., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Sugen5416 (semaxinib) is an inhibitor of the vascular endothelial growth factor (VEGF) receptor. A rat model of Pulmonary Arterial Hypertension (PAH), created with Sugen5416 and chronic hypoxia, is known to have similar histological findings to those of PAH patients., Objective: To evaluate the pathophysiological mechanisms of cardiac remodeling due to hypoxic stress with Sugen5416 in vivo., Methods: Male Sprague-Dawley rats were exposed to hypoxia (10 ± 1% O2) for 2 weeks after a single injection of Sugen5416 (SU-hypoxia group) or the vehicle (V-hypoxia group)., Results: Hypoxia elevated right ventricular (RV) systolic pressure and caused RV remodeling on Day 14. By electron microscopy, metamorphosis of capillaries with endothelial cell occlusive degeneration was observed in the RV myocardium of the SU-hypoxia group from Day 3. After reoxygenation, progressive RV remodeling with extensive degeneration of cardiomyocytes was observed in the SUhypoxia group, associated with a significant increase of oxidative stress and TUNEL-positive cells in both RV and left ventricular myocardium on Day 84. The expression of VEGF mRNA in the RV myocardium was significantly suppressed in the SU-hypoxia group on Day 3, whereas delayed activation of VEGF/extracellular signal-regulated kinase (ERK) signaling pathway on Day 14 were observed., Conclusion: Capillary degeneration and activation of VEGF/ERK signaling pathway might be crucial to accelerate the cardiac remodeling due to hypoxic stress with Sugen5416., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Remote ischemic conditioning (RIC) by repeated treatment of transient limb ischemia is a clinically applicable method for protecting the heart against injury at the time of reperfusion. In this study, we investigated the effects of repeated RIC on cardiac dysfunction after myocardial infarction (MI)., Methods and Results: At 4weeks after MI, rats were separated into the untreated (UT) group or the RIC-treated group. RIC treatment was performed by 5cycles of 5min of bilateral hindlimb ischemia and 5min of reperfusion once a day for 4weeks. Despite comparable MI size, left ventricular (LV) ejection fraction (LVEF) was significantly improved in the RIC group compared with the UT group. Furthermore, the LVEF in the RIC group was improved, although not significantly, after treatment. RIC treatment also prevented the deterioration of LV diastolic function. MI-induced LV interstitial fibrosis in the boundary region and oxidant stress were significantly attenuated by RIC treatment. MicroRNA-29a (miR-29a), a key regulator of tissue fibrosis, was highly expressed in the exosomes and the marginal area of the RIC group. Even in the differentiated C2C12-derived exosomes, miR-29a expression was significantly increased under hypoxic condition. As well as miR-29a, insulin-like growth factor 1 receptor (IGF-1R) was highly expressed both in the exosomes and remote non-infarcted myocardium of the RIC group. IGF-1R expression was also increased in the C2C12-derived exosomes under hypoxic conditions., Conclusions: Repeated RIC reduces adverse LV remodeling and oxidative stress by MI. Exosome-mediated intercellular communication may contribute to the beneficial effect of RIC treatment., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The prevalence of sleep apnea is very high in patients with heart failure (HF). The aims of this study were to investigate the influence of intermittent hypoxia (IH) on the failing heart and to evaluate the antioxidant effect of hydrogen gas. Normal male Syrian hamsters (n = 22) and cardiomyopathic (CM) hamsters (n = 33) were exposed to IH (repeated cycles of 1.5 min of 5% oxygen and 5 min of 21% oxygen for 8 h during the daytime) or normoxia for 14 days. Hydrogen gas (3.05 vol/100 vol) was inhaled by some CM hamsters during hypoxia. IH increased the ratio of early diastolic mitral inflow velocity to mitral annulus velocity (E/e', 21.8 vs. 16.9) but did not affect the LV ejection fraction (EF) in normal Syrian hamsters. However, IH increased E/e' (29.4 vs. 21.5) and significantly decreased the EF (37.2 vs. 47.2%) in CM hamsters. IH also increased the cardiomyocyte cross-sectional area (672 vs. 443 μm(2)) and interstitial fibrosis (29.9 vs. 9.6%), along with elevation of oxidative stress and superoxide production in the left ventricular (LV) myocardium. Furthermore, IH significantly increased the expression of brain natriuretic peptide, β-myosin heavy chain, c-fos, and c-jun mRNA in CM hamsters. Hydrogen gas inhalation significantly decreased both oxidative stress and embryonic gene expression, thus preserving cardiac function in CM hamsters. In conclusion, IH accelerated LV remodeling in CM hamsters, at least partly by increasing oxidative stress in the failing heart. These findings might explain the poor prognosis of patients with HF and sleep apnea., (Copyright © 2014 the American Physiological Society.)

Long-acting Ca(2+)-channel blockers have been reported to be effective in treating ischemic heart disease. However, their effects on cardiac remodeling after myocardial infarction (MI) are still unclear. We performed this study to examine the effect of azelnidipine on left ventricular (LV) remodeling, including systolic and diastolic dysfunction, in rats with MI. MI was induced by ligation of the left anterior descending artery. The rats were then separated into 3 groups: a sham-operated group (n = 9), untreated MI group (n = 10), and azelnidipine-treated MI group (n = 10). Four weeks after MI, hemodynamic measurements and Doppler echocardiographic assessment were performed. LV weight and LV end-diastolic dimension were significantly higher in the untreated MI group than in the sham-operated group. Azelnidipine significantly prevented the increases in these parameters. Azelnidipine also improved the ejection fraction (42 +/- 3%, P<0.05) and the E wave to A wave ratio (3.2 +/- 0.5, P<0.05), compared with the untreated MI group (31 +/- 3% and 5.3 +/- 0.8, respectively). In conclusion, azelnidipine can prevent LV remodeling and improve systolic and diastolic function after MI. Administration of long-acting Ca(2+)-channel blockers after MI is an effective strategy for treating MI.

Background: Myocardial infarction (MI) promotes deleterious remodeling of the myocardium, resulting in ventricular dilation and pump dysfunction. Supplementing infarcted myocardium with neonatal myocyte would attenuate deleterious remodeling and so the present study used Doppler echocardiography and histology to analyze the cardiac function and histological regeneration of the damaged myocardium after cellular cardiomyoplasty., Methods and Results: Experimental MI was induced by 24-h coronary ligation followed by reperfusion in adult male Lewis rats and neonatal myocytes were injected directly into the infarct and peri-infarct regions. Three groups of animals were studied at 4 weeks after cellular cardiomyoplasty: noninfarcted control (control), MI plus sham injection (MI), and MI plus cell injection (MI + cell). Ventricular remodeling and cardiac performance were assessed by Doppler echocardiography or contrast echocardiography. At 4 weeks after cellular cardiomyoplasty, MI + cell hearts exhibited attenuation of global ventricular dilation and cardiac function compared with MI hearts not receiving cellular cardiomyoplasty. Immunohistochemically, connexin-43-positive small cells were observed in the vicinity of the infarction in MI + cell heart. By electron microscopy, these cells contained myofilaments with Z-bands and poorly developed intercalated disks, suggesting neonatal myocardial cells. Furthermore, the myocardial cells were often making close contact with interstitial cells., Conclusions: Implanted neonatal myocytes form viable grafts after MI, resulting in attenuated ventricular dilation and enhanced contractile function. Echocardiography, electron microscopy, and immunohistochemistry are useful methods for assessing the functional and histological regeneration of the damaged myocardium.

Multiple lines of evidence establish that angiotensin II (Ang II) induces not only hypertension but also directly contributes to cardiac diseases. Apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, plays a key role in stress-induced cellular responses. However, nothing is known about the role of ASK1 in cardiac hypertrophy and remodeling in vivo. In this study, by using mice deficient in ASK1 (ASK1-/- mice), we investigated the role of ASK1 in cardiac hypertrophy and remodeling induced by Ang II. Left ventricular (LV) ASK1 was activated by Ang II infusion in wild-type mice, which was mediated by angiotensin II type 1 receptor and superoxide. Although Ang II-induced hypertensive effect was comparable to wild-type and ASK1-/- mice, LV ASK1 activation by Ang II was not detectable in ASK1-/- mice, and p38 and c-Jun N-terminal kinase (JNK) activation was lesser in ASK-/- mice than in wild-type mice. Elevation of blood pressure by continuous Ang II infusion was comparable between ASK1-/- and wild-type mice. However, Ang II-induced cardiac hypertrophy and remodeling, including cardiomyocyte hypertrophy, cardiac hypertrophy-related mRNA upregulation, cardiomyocyte apoptosis, interstitial fibrosis, coronary arterial remodeling, and collagen gene upregulation, was significantly attenuated in ASK1-/- mice compared with wild-type mice. These results provided the first in vivo evidence that ASK1 is the critical signaling molecule for Ang II-induced cardiac hypertrophy and remodeling. Thus, ASK1 is proposed to be a potential therapeutic target for cardiac diseases.