Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease.
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ABSTRACT:
SUBMITTER: Kovacs MG
PROVIDER: S-EPMC8657420 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized to the EXP3179 and EXP3174 metabolites, reduces myocardial fibrosis and LV stiffness in hypertensive patients. Our aim was to investigate the differential influence of losartan metabolites on myocardial LOX and CCL in an experimental model of hypertension with myocardial fibrosis, and whether EXP3179 and EXP3174 modify LOX expression and activity in fibroblasts. In rats treated with NG-nitro-L-arginine methyl ester (L-NAME), administration of EXP3179 fully prevented LOX, CCL and connective tissue growth factor (CTGF) increase, as well as fibrosis, without normalization of blood pressure (BP). In contrast, administration of EXP3174 normalized BP and attenuated fibrosis but did not modify LOX, CCL and CTGF. In TGF-β1-stimulated fibroblasts, EXP3179 inhibited CTGF and LOX expression and activity with lower IC50 values than EXP3174. Our results indicate that, despite a lower antihypertensive effect, EXP3179 shows higher anti-fibrotic efficacy than EXP3174, likely through its ability to prevent the excess of LOX and CCL. It is suggested that the anti-fibrotic effect of EXP3179 may be partially mediated by the blockade of CTGF-induced LOX in fibroblasts.
| S-EPMC5291109 | biostudies-literature
Project description:BACKGROUND:Stimulation of sGC (soluble guanylate cyclase) or inhibition of PDE5 (phosphodiesterase type 5) activates PKG (protein kinase G)-1? to counteract cardiac hypertrophy and failure. PKG1? acts within localized intracellular domains; however, its oxidation at cysteine 42, linking homomonomers, alters this localization, impairing suppression of pathological cardiac stress. Because PDE5 and sGC reside in separate microdomains, we speculated that PKG1? oxidation might also differentially influence the effects from their pharmacological modulation. METHODS AND RESULTS:Knock-in mice expressing a redox-dead PKG1? (PKG1?C42S) or littermate controls (PKG1?WT) were subjected to transaortic constriction to induce pressure overload and treated with a PDE5 inhibitor (sildenafil), sGC activator (BAY602770 [BAY]), or vehicle. In PKG1?WT controls, sildenafil and BAY similarly enhanced PKG activity and reduced pathological hypertrophy/fibrosis and cardiac dysfunction after transaortic constriction. However, sildenafil failed to protect the heart in PKG1?C42S, unlike BAY, which activated PKG and thereby facilitated protective effects. This corresponded with minimal PDE5 activation in PKG1?C42S exposed to transaortic constriction versus higher activity in controls and little colocalization of PDE5 with PKG1?C42S (versus colocalization with PKG1?WT) in stressed myocytes. CONCLUSIONS:In the stressed heart and myocytes, PKG1? C42-disulfide formation contributes to PDE5 activation. This augments the pathological role of PDE5 and so in turn enhances the therapeutic impact from its inhibition. PKG1? oxidation does not change the benefits from sGC activation. This finding favors the use of sGC activators regardless of PKG1? oxidation and may help guide precision therapy leveraging the cyclic GMP/PKG pathway to treat heart disease.
| S-EPMC5858464 | biostudies-literature
Project description:BackgroundThe use of Adriamycin (ADR), also known as doxorubicin, as a chemotherapy agent is limited by its detrimental adverse effects, especially cardiotoxicity. Recent studies have emphasized the crucial role of angiotensin II (Ang-II) in the development of ADR-induced cardiomyopathy. This study aimed to explore the potential cardioprotective effects of losartan in a rat model of ADR-induced cardiomyopathy.MethodsMale Sprague-Dawley rats were randomly divided into 3 groups: a control group (group C), an ADR-treated group (ADR 5 mg/kg/wk for 3 weeks via intraperitoneal injections; group A), and co-treatment of ADR with losartan group (same dose of ADR and losartan; 10 mg/kg/day per oral for 3 weeks; group L). Western blot analysis was conducted to demonstrate changes in brain natriuretic peptide, collagen 1, tumor necrosis factor (TNF)-α, interleukin-6, matrix metalloproteinase (MMP)-2, B-cell leukemia/lymphoma (Bcl)-2, Bcl-2-associated X (Bax), and caspase-3 protein expression levels in left ventricular (LV) tissues from each group.ResultsLosartan administration reduced LV hypertrophy, collagen content, and the expression of pro-inflammatory factors TNF-α and MMP-2 in LV tissue. In addition, losartan led to a decrease in the expression of the pro-apoptotic proteins Bax and caspase-3 and an increase in the expression of the anti-apoptotic protein Bcl-2. Moreover, losartan treatment induced a reduction in the apoptotic area compared to group A.ConclusionIn an ADR-induced cardiomyopathy rat model, co-administration of ADR with losartan presented cardioprotective effects by attenuating LV hypertrophy, pro-inflammatory factors, and apoptosis in LV tissue.
| S-EPMC10480395 | biostudies-literature
Project description:Radiation therapy for the treatment of thoracic cancers may be associated with radiation-induced heart disease (RIHD), especially in long-term cancer survivors. Mechanisms by which radiation causes heart disease are largely unknown. To identify potential long-term contributions of mitochondria in the development of radiation-induced heart disease, we examined the time course of effects of irradiation on cardiac mitochondria. In this study, Sprague-Dawley male rats received image-guided local X irradiation of the heart with a single dose ranging from 3-21 Gy. Two weeks after irradiation, left ventricular mitochondria were isolated to assess the dose-dependency of the mitochondrial permeability transition pore (mPTP) opening in a mitochondrial swelling assay. At time points from 6 h to 9 months after a cardiac dose of 21 Gy, the following analyses were performed: left ventricular Bax and Bcl-2 protein levels; apoptosis; mitochondrial inner membrane potential and mPTP opening; mitochondrial mass and expression of mitophagy mediators Parkin and PTEN induced putative kinase-1 (PINK-1); mitochondrial respiration and protein levels of succinate dehydrogenase A (SDHA); and the 70 kDa subunit of complex II. Local heart irradiation caused a prolonged increase in Bax/Bcl-2 ratio and induced apoptosis between 6 h and 2 weeks. The mitochondrial membrane potential was reduced until 2 weeks, and the calcium-induced mPTP opening was increased from 6 h up to 9 months. An increased mitochondrial mass together with unaltered levels of Parkin suggested that mitophagy did not occur. Lastly, we detected a significant decrease in succinate-driven state 2 respiration in isolated mitochondria from 2 weeks up to 9 months after irradiation, coinciding with reduced mitochondrial levels of succinate dehydrogenase A. Our results suggest that local heart irradiation induces long-term changes in cardiac mitochondrial membrane functions, levels of SDH and state 2 respiration. At any time after exposure to radiation, cardiac mitochondria are more prone to mPTP opening. Future studies will determine whether this makes the heart more susceptible to secondary stressors such as calcium overload or ischemia/reperfusion.
| S-EPMC4029615 | biostudies-literature
Project description:Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (β3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the β3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, β3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the β3-AR.
| S-EPMC8410807 | biostudies-literature
Project description:Cardiovascular diseases (CVDs) account for the majority of deaths worldwide. Radiation-induced heart diseases (RIHD) is one of the side effects following exposure to ionizing radiation (IR). Exposure could be from various forms such as diagnostic imaging, radiotherapy for cancer treatment, as well as nuclear disasters and nuclear accidents. RIHD is mostly observed after radiotherapy for thoracic malignancies, especially left breast cancer. RIHD may affect the supply of blood to heart muscles, leading to an increase in the risk of heart attacks to irradiated persons. Due to its dose-limiting consequence, RIHD has a negative effect on the therapeutic efficacy of radiotherapy. Several methods have been proposed for protection against RIHD. In this paper, we review the use of natural products, which have shown promising results for protection against RIHD.
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Project description:Zinc-α2-glycoprotein (AZGP1) is a secreted protein synthesized by epithelial cells and adipocytes that has roles in lipid metabolism, cell cycling, and cancer progression. Our previous findings in AKI indicated a new role for AZGP1 in the regulation of fibrosis, which is a unifying feature of CKD. Using two models of chronic kidney injury, we now show that mice with genetic AZGP1 deletion develop significantly more kidney fibrosis. This destructive phenotype was rescued by injection of recombinant AZGP1. Exposure of AZGP1-deficient mice to cardiac stress by thoracic aortic constriction revealed that antifibrotic effects were not restricted to the kidney but were cardioprotective. In vitro, recombinant AZGP1 inhibited kidney epithelial dedifferentiation and antagonized fibroblast activation by negatively regulating TGF-β signaling. Patient sera with high levels of AZGP1 similarly attenuated TGF-β signaling in fibroblasts. Taken together, these findings indicate a novel role for AZGP1 as a negative regulator of fibrosis progression, suggesting that recombinant AZGP1 may have translational effect for treating fibrotic disease.
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Project description:Childhood radiation exposure is a known thyroid cancer risk factor. This study evaluated the effects of age on radiation-induced thyroid carcinogenesis in rats irradiated with 8 Gy X-rays. We analyzed cell proliferation, cell death, DNA damage response, and autophagy-related markers in 4-week-old (4W) and 7-month-old (7M) rats and the incidence of thyroid tumors in 4W, 4-month-old (4M), and 7M rats 18 months after irradiation. Cell death and DNA damage response were increased in 4W rats compared to those in controls at 1 month post-irradiation. More Ki-67-positive cells were observed in 4W rats at 12 months post-irradiation. Thyroid tumors were confirmed in 61.9% (13/21), 63.6% (7/11), and 33.3% (2/6) of irradiated 4W, 4M, and 7M rats, respectively, compared to 0%, 14.3% (1/7), and 16.7% (1/6) in the respective nonirradiated controls. There were 29, 9, and 2 tumors in irradiated 4W, 4M, and 7M rats, respectively. The expression of several autophagy components was downregulated in the area surrounding radiation-induced thyroid carcinomas in 4W and 7M rats. LC3 and p62 expression levels decreased in radiation-induced follicular carcinoma in 4W rats. Radiosensitive cells causing thyroid tumors may be more prevalent in young rats, and abrogation of autophagy may be associated with radiation-induced thyroid carcinogenesis.
| S-EPMC8476610 | biostudies-literature
Project description:Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator that antagonizes cardiac hypertrophy.Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs) or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an antihypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1(cko)). When subjected to 2 weeks of pressure overload, Pak1(cko) mice developed greater cardiac hypertrophy with attendant blunting of JNK activation compared with controls, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. Chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1(cko) mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analog, was able to prevent pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. Meanwhile, FTY720 failed to exert such an effect on Pak1(cko) mice, suggesting that the antihypertrophic effect of FTY720 likely acts through Pak1 activation.These results, for the first time, establish Pak1 as a novel antihypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.
| S-EPMC3242076 | biostudies-literature
Project description:Fractionated radiation therapy is believed to reoxygenate and subsequently radiosensitize surviving hypoxic cancer cells. Measuring tumor reoxygenation between radiation fractions could conceivably provide an early biomarker of treatment response. However, the relationship between tumor reoxygenation and local control is not well understood. We used noninvasive optical fiber-based diffuse reflectance spectroscopy to monitor radiation-induced changes in hemoglobin oxygen saturation (sO2) in tumor xenografts grown from two head and neck squamous cell carcinoma cell lines - UM-SCC-22B and UM-SCC-47. Tumors were treated with 4 doses of 2 Gy over 2 consecutive weeks and diffuse reflectance spectra were acquired every day during the 2-week period. There was a statistically significant increase in sO2 in the treatment-responsive UM-SCC-22B tumors immediately following radiation. This reoxygenation trend was due to an increase in oxygenated hemoglobin (HbO2) and disappeared over the next 48 h as sO2 returned to preradiation baseline values. Conversely, sO2 in the relatively radiation-resistant UM-SCC-47 tumors increased after every dose of radiation and was driven by a significant decrease in deoxygenated hemoglobin (dHb). Immunohistochemical analysis revealed significantly elevated expression of hypoxia-inducible factor (HIF-1) in the UM-SCC-47 tumors prior to radiation and up to 48 h postradiation compared with the UM-SCC-22B tumors. Our observation of a decrease in dHb, a corresponding increase in sO2, as well as greater HIF-1α expression only in UM-SCC-47 tumors strongly suggests that the reoxygenation within these tumors is due to a decrease in oxygen consumption in the cancer cells, which could potentially play a role in promoting radiation resistance.
| S-EPMC7683290 | biostudies-literature