Ang II Promotes Cardiac Autophagy and Hypertrophy via Orai1/STIM1.
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ABSTRACT:
SUBMITTER: Zheng CB
PROVIDER: S-EPMC8165566 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPathological cardiac hypertrophy is a major risk factor for cardiovascular diseases, including heart failure. However, limited pharmacological therapies are available for reversing the maladaptive process and restoring cardiac function. Citri reticulatae Pericarpium (CRP) has been used in traditional Chinese medicine prescriptions for clinical treatment. Previous studies have shown that CRP and its ingredients have beneficial effects on the cardiovascular system. However, whether CRP has a protective effect against pathological cardiac hypertrophy remains unknown.MethodsPrimary neonatal rat cardiomyocytes (NRCMs) were treated with angiotensin II (Ang II) to induce pathological hypertrophy in vitro. Immunofluorescent staining and quantitative real-time PCR (qRT-PCR) were used to determine the cell size and the expression of hypertrophic gene markers (Anp and Bnp), respectively. Male C57BL/6 mice were subjected to the investigation of cardiac hypertrophy induced by Ang II (2.5 mg/kg/d for 4 weeks). CRP (0.5 g/kg/d for 4 weeks) was administrated to treat mice with or without peroxisome proliferator-activated receptors gamma (PPARγ) inhibitor T0070907 (1 mg/kg/d for 4 weeks treatment) infused with Ang II. Cardiac hypertrophy (hematoxylin-eosin staining and qRT-PCR), fibrosis (Masson's Trichrome staining, qRT-PCR, and western blot), and cardiac function (echocardiography) were examined in these mice. Western blot was used to determine the protein level of PPARγ and PGC-1α both in NRCMs and in mice.ResultsWe found that CRP could prevent Ang II-induced pathological cardiac hypertrophy evidenced by improving cardiac function, decreasing hypertrophic growth and reducing cardiac fibrosis. Also, we demonstrated that PPARγ was upregulated by CRP both in NRCMs and in hearts. Moreover, PPARγ inhibitor could abolish the inhibitory effects of CRP on Ang II-induced pathological cardiac hypertrophy.ConclusionsCRP attenuates Ang II-induced pathological cardiac hypertrophy by activating PPARγ.
| S-EPMC7575934 | biostudies-literature
Project description:Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and regulated by various signalling pathways. Recently, we observed that mouse embryonic fibroblasts from CD38 knockout mice were significantly resistant to oxidative stress such as H2 O2 -induced injury and hypoxia/reoxygenation-induced injury. In addition, we also found that CD38 knockout mice protected heart from ischaemia reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. However, the role of CD38 in cardiac hypertrophy is not explored. Here, we investigated the roles and mechanisms of CD38 in angiotensin II (Ang-II)-induced cardiac hypertrophy. Following 14 days of Ang-II infusion with osmotic mini-pumps, a comparable hypertension was generated in both of CD38 knockout and wild-type mice. However, the cardiac hypertrophy and fibrosis were much more severe in wild-type mice compared with CD38 knockout mice. Consistently, RNAi-induced knockdown of CD38 decreased the gene expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and reactive oxygen species generation in Ang-II-stimulated H9c2 cells. In addition, the expression of SIRT3 was elevated in CD38 knockdown H9c2 cells, in which SIRT3 may further activate the FOXO3 antioxidant pathway. The intracellular Ca2+ release induced by Ang-II markedly decreased in CD38 knockdown H9c2 cells, which might be associated with the decrease of nuclear translocation of NFATc4 and inhibition of ERK/AKT phosphorylation. We concluded that CD38 plays an essential role in cardiac hypertrophy probably via inhibition of SIRT3 expression and activation of Ca2+ -NFAT signalling pathway. Thus, CD38 may be a novel target for treating cardiac hypertrophy.
| S-EPMC5542907 | biostudies-literature
Project description:AimIn this work, we explored the role of corosolic acid (CRA) during pressure overload-induced cardiac hypertrophy.Methods and resultsCardiac hypertrophy was induced in mice by aortic banding. Four weeks post-surgery, CRA-treated mice developed blunted cardiac hypertrophy, fibrosis, and dysfunction, and showed increased LC3 II and p-AMPK expression. In line with the in vivo studies, CRA also inhibited the hypertrophic response induced by PE stimulation accompanying with increased LC3 II and p-AMPK expression. It was also found that CRA blunted cardiomyocyte hypertrophy and promoted autophagy in Angiotensin II (Ang II)-treated H9c2 cells. Moreover, to further verify whether CRA inhibits cardiac hypertrophy by the activation of autophagy, blockade of autophagy was achieved by CQ (an inhibitor of the fusion between autophagosomes and lysosomes) or 3-MA (an inhibitor of autophagosome formation). It was found that autophagy inhibition counteracts the protective effect of CRA on cardiac hypertrophy. Interestingly, AMPK knockdown with AMPK?2 siRNA-counteracted LC3 II expression increase and the hypertrophic response inhibition caused by CRA in PE-treated H9c2 cells.ConclusionThese results suggest that CRA may protect against cardiac hypertrophy through regulating AMPK-dependent autophagy.
| S-EPMC6893168 | biostudies-literature
Project description:Hypertension is one of the common causes of pathological cardiac hypertrophy and a major risk for morbidity and mortality of cardiovascular diseases worldwide. Ubiquitin-Specific Protease 7 (USP7), the first identified deubiquitinating enzymes, participated in a variety of biological processes, such as cell proliferation, DNA damage response, tumourigenesis, and apoptosis. However, its role and mechanism in cardiac remodeling remain unclear. Here, our data indicated that USP7 expression was increased during Ang II-induced cardiac hypertrophy and remodeling in mice and humans with heart failure, while the administration of its inhibitor p22077 attenuated cardiac hypertrophy, cardiac fibrosis, inflammation, and oxidase stress. Mechanistically, the administration of p22077 inhibited the multiple signaling pathways, including AKT/ERK, TGF-β/SMAD2/Collagen I/Collagen III, NF-κB/NLRP3, and NAPDH oxidases (NOX2 and NOX4). Taken together, these findings demonstrate that USP7 may be a new therapeutic target for hypertrophic remodeling and HF.
| S-EPMC9640964 | biostudies-literature
Project description:Reduction of expression and activity of sirtuin 3 (SIRT3) contributes to the pathogenesis of cardiomyopathy via inducing mitochondrial injury and energy metabolism disorder. However, development of effective ways and agents to modulate SIRT3 remains a big challenge. In this study we explored the upstream suppressor of SIRT3 in angiotensin II (Ang II)-induced cardiac hypertrophy in mice. We first found that SIRT3 deficiency exacerbated Ang II-induced cardiac hypertrophy, and resulted in the development of spontaneous heart failure. Since miRNAs play crucial roles in the pathogenesis of cardiac hypertrophy, we performed miRNA sequencing on myocardium tissues from Ang II-infused Sirt3-/- and wild type mice, and identified microRNA-214 (miR-214) was significantly up-regulated in Ang II-infused mice. Similar results were also obtained in Ang II-treated neonatal mouse cardiomyocytes (NMCMs). Using dual-luciferase reporter assay we demonstrated that SIRT3 was a direct target of miR-214. Overexpression of miR-214 in vitro and in vivo decreased the expression of SIRT3, which resulted in extensive mitochondrial damages, thereby facilitating the onset of hypertrophy. In contrast, knockdown of miR-214 counteracted Ang II-induced detrimental effects via restoring SIRT3, and ameliorated mitochondrial morphology and respiratory activity. Collectively, these results demonstrate that miR-214 participates in Ang II-induced cardiac hypertrophy by directly suppressing SIRT3, and subsequently leading to mitochondrial malfunction, suggesting the potential of miR-214 as a promising intervention target for antihypertrophic therapy.
| S-EPMC8379271 | biostudies-literature
Project description:Rationale: Sustained cardiac hypertrophy often leads to heart failure (HF). Understanding the regulation of cardiomyocyte growth is crucial for the treatment of adverse ventricular remodeling and HF. Cell division cycle 20 (CDC20) is an anaphase-promoting complex activator that is essential for cell division and tumorigenesis, but the role of CDC20 in cardiac hypertrophy is unknown. We aimed to test whether CDC20 participates in the regulation of pathological cardiac hypertrophy and investigate the underlying mechanism in vitro and in vivo. Methods: Male C57BL/6 mice were administered a recombinant adeno-associated virus serotype 9 (rAAV9) vector expressing CDC20 or a siRNA targeting CDC20 and their respective controls by tail intravenous injection. Results: Microarray analysis showed that CDC20 was significantly upregulated in the heart after angiotensin II infusion. Knockdown of CDC20 in cardiomyocytes and in the heart reduced cardiac hypertrophy upon agonist stimulation or transverse aortic constriction (TAC). Conversely, enforced expression of CDC20 in cardiomyocytes and in the heart aggravated the hypertrophic response. Furthermore, we found that CDC20 directly targeted LC3, a key regulator of autophagy, and promoted LC3 ubiquitination and degradation by the proteasome, which inhibited autophagy leading to hypertrophy. Moreover, knockdown of LC3 or inhibition of autophagy attenuated Ang II-induced cardiomyocyte hypertrophy after deletion of CDC20 in vitro. Conclusions: Our study reveals a novel cardiac hypertrophy regulatory mechanism that involves CDC20, LC3 and autophagy, and suggests that CDC20 could be a new therapeutic target for patients with hypertrophic heart diseases.
| S-EPMC6299438 | biostudies-literature
Project description:Cardiac hypertrophy (CH) is characterized by an increase in cardiomyocyte size, and is the most common cause of cardiac-related sudden death. A decrease in gap junction (GJ) coupling and mitochondrial dysfunction are important features of CH, but the mechanisms of decreased coupling and energy impairment are poorly understood. It has been reported that GJA1-20k has a strong tropism for mitochondria and is required for the trafficking of connexin 43 (Cx43) to cell-cell borders. In this study, we investigated the effects of GJA1-20k on Cx43 GJ coupling and mitochondrial function in the pathogenesis of CH. We performed hematoxylin-eosin (HE) and Masson staining, and observed significant CH in 18-week-old male spontaneously hypertensive rats (SHRs) compared to age-matched normotensive Wistar-Kyoto (WKY) rats. In cardiomyocytes from SHRs, the levels of Cx43 at the intercalated disc (ID) and the expression of GJA1-20k were significantly reduced, whereas JAK-STAT signaling was activated. Furthermore, the SHR rats displayed suppressed mitochondrial GJA1-20k and mitochondrial biogenesis. Administration of valsartan (10 mg· [Formula: see text] d-1, i.g., for 8 weeks) prevented all of these changes. In neonatal rat cardiomyocytes (NRCMs), overexpression of GJA1-20k attenuated Ang II-induced cardiomyocyte hypertrophy and caused elevated levels of GJ coupling at the cell-cell borders. Pretreatment of NRCMs with the Jak2 inhibitor AG490 (10 µM) blocked Ang II-induced reduction in GJA1-20k expression and Cx43 gap junction formation; knockdown of Jak2 in NRCMs significantly lessened Ang II-induced cardiomyocyte hypertrophy and normalized GJA1-20k expression and Cx43 gap junction formation. Overexpression of GJA1-20k improved mitochondrial membrane potential and respiration and lowered ROS production in Ang II-induced cardiomyocyte hypertrophy. These results demonstrate the importance of GJA1-20k in regulating gap junction formation and mitochondrial function in Ang II-induced cardiomyocyte hypertrophy, thus providing a novel therapeutic strategy for patients with cardiomyocyte hypertrophy.
| S-EPMC8115281 | biostudies-literature
Project description:BACKGROUND:Stromal interaction molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiomyocytes. STIM1 is thought to act as an initiator of cardiac hypertrophic response at the level of the sarcolemma, but the pathways underpinning this effect have not been examined. METHODS AND RESULTS:To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiomyocytes by using in vivo gene delivery of specific short hairpin RNAs. In 3 different models, we found that Stim1 silencing prevents the development of pressure overload-induced hypertrophy but also reverses preestablished cardiac hypertrophy. Reduction in STIM1 expression promoted a rapid transition to heart failure. We further showed that Stim1 silencing resulted in enhanced activity of the antihypertrophic and proapoptotic GSK-3? molecule. Pharmacological inhibition of glycogen synthase kinase-3 was sufficient to reverse the cardiac phenotype observed after Stim1 silencing. At the level of ventricular myocytes, Stim1 silencing or inhibition abrogated the capacity for phosphorylation of Akt(S473), a hydrophobic motif of Akt that is directly phosphorylated by mTOR complex 2. We found that Stim1 silencing directly impaired mTOR complex 2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTOR complex 2. CONCLUSIONS:These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiomyocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2, which further results in repression of GSK-3? activity.
| S-EPMC4829441 | biostudies-literature
Project description: Not available
| S-EPMC10950121 | biostudies-literature
Project description:Store-operated calcium entry (SOCE) is a major pathway for calcium ions influx into cells and has a critical role in various cell functions. Here we demonstrate that calcium-bound calmodulin (Ca2+-CaM) binds to the core region of activated STIM1. This interaction facilitates slow Ca2+-dependent inactivation after Orai1 channel activation by wild-type STIM1 or a constitutively active STIM1 mutant. We define the CaM-binding site in STIM1, which is adjacent to the STIM1-Orai1 coupling region. The binding of Ca2+-CaM to activated STIM1 disrupts the STIM1-Orai1 complex and also disassembles STIM1 oligomer. Based on these results we propose a model for the calcium-bound CaM-regulated deactivation of SOCE.
| S-EPMC5648805 | biostudies-literature