Application of fosl1-il-6 signal loop in treatment of stress cardiomyopathy

Abstract

This invention discloses the application of the FOSL1-IL-6 signaling loop in the treatment of stress cardiomyopathy, belonging to the field of biomedicine. This invention reveals for the first time the core role of the FOSL1-IL-6 positive feedback signal axis in the pathogenesis of stress cardiomyopathy, and provides two effective treatment strategies based on this mechanism (targeting FOSL1 or IL-6R), providing a novel strategy for the treatment of stress cardiomyopathy.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to the application of substances targeting the FOSL1-IL-6 signaling circuit in the treatment of stress cardiomyopathy, particularly the use of substances that inhibit FOSL1 or block the IL-6 (interleukin-6) / IL-6R (IL-6 receptor) signaling pathway to treat stress cardiomyopathy. Background Technology

[0002] Stress cardiomyopathy (SC), also known as broken heart syndrome or Takotsubo syndrome, is an acute, reversible heart failure syndrome triggered by intense emotional or physiological stress. Its clinical manifestations are similar to those of acute myocardial infarction, but coronary angiography usually shows no significant obstruction. Currently, the pathogenesis of stress cardiomyopathy is not fully understood, and there are no specific drugs for treatment in clinical practice; treatment mainly relies on supportive care. Therefore, there is an urgent clinical need to further explore the molecular pathological mechanisms of stress cardiomyopathy and develop targeted treatment strategies.

[0003] Existing research indicates that excessive sympathetic nerve activation and its downstream effects are core drivers of stress-induced cardiomyopathy. The catecholamine storm is considered a key factor leading to myocardial stunning. However, the specific molecular bridges from the catecholamine storm to myocardial injury remain to be elucidated. In recent years, the role of inflammatory responses, particularly the cytokine storm, in various cardiovascular diseases has received increasing attention. Studies show that the inflammatory cytokine IL-6 is not only significantly elevated in patients with stress-induced cardiomyopathy but is also closely related to adverse cardiovascular events and mortality, suggesting that IL-6 is highly likely involved in disease development and progression, influencing disease outcomes.

[0004] On the other hand, endothelial dysfunction and microcirculatory disturbances are also considered important pathological factors in stress-induced cardiomyopathy. FOSL1, as a member of the AP-1 transcription factor family, has been shown to play a crucial role in endothelial cell function, vascular remodeling, and myocardial fibrosis. However, whether FOSL1 is involved in the pathogenesis of stress-induced cardiomyopathy remains unknown. Previous studies have found that FOSL1 can bind to the IL-6 promoter region, promoting IL-6 transcription. IL-6, in turn, can promote FOSL1 deacetylation, thereby enhancing its transcriptional activity. However, the association between the FOSL1-IL-6 regulatory loop and the development of stress-induced cardiomyopathy has not yet been reported.

[0005] In summary, although studies have pointed to the roles of inflammation (IL-6) and transcriptional regulation (FOSL1) in cardiovascular injury, the interaction network, causal relationship, and potential as combined or independent therapeutic targets of these two factors in the specific pathological state of stress cardiomyopathy have not been disclosed or revealed by any existing technology. Summary of the Invention

[0006] This invention discovers that FOSL1 and IL-6 are upregulated in multiple dimensions in a stress-induced cardiomyopathy model, and that they form a bidirectional positive feedback regulatory loop in stress-induced cardiomyopathy. Based on this, a novel molecular mechanism-based treatment strategy for stress-induced cardiomyopathy is developed.

[0007] The specific technical solution of the present invention is as follows: In a first aspect, the present invention provides the use of a substance targeting the FOSL1-IL-6 signaling loop in the preparation of a medicament for treating stress-induced cardiomyopathy, wherein the substance is capable of inhibiting FOSL1 or blocking the IL-6 / IL-6R signaling pathway.

[0008] In the above applications, substances that can inhibit FOSL1 are FOSL1 inhibitors, including but not limited to siRNA, shRNA, or antisense oligonucleotides that can knock down FOSL1 expression.

[0009] In the above applications, substances capable of blocking the IL-6 / IL-6R signaling pathway are inhibitors of the IL-6 / IL-6R signaling pathway, including but not limited to anti-IL-6R monoclonal antibodies. For example, in some embodiments of the present invention, the anti-IL-6R monoclonal antibody is tocilizumab (TOC).

[0010] In the above applications, in addition to substances that target the FOSL1-IL-6 signaling loop, the drug may also contain pharmaceutically acceptable excipients.

[0011] Secondly, the present invention provides a drug for treating stress-induced cardiomyopathy, which contains at least an active ingredient that inhibits FOSL1 expression; furthermore, in order to improve the therapeutic effect, other active ingredients that can treat stress-induced cardiomyopathy may be added.

[0012] In the aforementioned drugs, the active ingredients that inhibit FOSL1 expression are siRNA, shRNA, and / or antisense oligonucleotides that knock down FOSL1 expression.

[0013] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. For the first time, a direct causal link between the FOSL1-IL-6 signaling loop and stress-induced cardiomyopathy was established.

[0014] This invention, for the first time, systematically demonstrates the synergistic upregulation of FOSL1 and IL-6 in a classic isoproterenol (ISO)-induced stress cardiomyopathy model and elucidates the molecular mechanism of mutual positive regulation between the two. This provides a novel, endogenous pathological mechanism explanation for stress cardiomyopathy, rather than being secondary to other serious diseases.

[0015] 2. The dual-targeting strategy was proposed and validated for the first time.

[0016] This invention not only validates the independent therapeutic effects of FOSL1 knockdown and IL-6R blockade on stress-induced cardiomyopathy, but more importantly, by revealing the FOSL1-IL-6 positive feedback loop, it provides a solid theoretical foundation for potential future combination therapies or the search for common upstream regulators of this loop. This mechanism-based, dual-target therapeutic approach is unprecedented.

[0017] 3. It expands the indications for tocilizumab.

[0018] Although tocilizumab has been approved for diseases such as rheumatoid arthritis and cytokine release syndrome, its application in treating classic isoproterenol-induced stress cardiomyopathy represents a significant breakthrough in this invention. While there are case reports of tocilizumab treatment for transient cardiomyopathy following a cytokine storm induced by SARS-CoV-2 infection, these are isolated cases secondary to severe viral infection, lacking typical cardiac marker abnormalities (such as troponin I and B-type natriuretic peptide), and whether this cardiomyopathy is equivalent to classic stress cardiomyopathy remains controversial. More importantly, these reports do not explore any molecular mechanisms, particularly failing to elucidate the relationship between IL-6 and FOSL1, and do not propose the use of IL-6R blockers for the treatment of classic stress cardiomyopathy. Attached Figure Description

[0019] To more clearly illustrate the technical solution of the present invention, the accompanying drawings used in the present invention will be briefly described below. Obviously, the drawings described below are merely some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.

[0020] Figure 1 This is a schematic diagram of the experimental procedure for constructing and detecting the stress cardiomyopathy mouse model in Example 1; Figure 2The images show the echocardiographic results of the stress-induced cardiomyopathy mouse model in Example 1. A represents representative B-mode echocardiographic images (diastole and systole) at different time points, BC represents the temporal trends of left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and DE represents the temporal trends of left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). Figure 3 The results of plasma biomarker detection in the stress cardiomyopathy mouse model in Example 1 are shown. A represents the trend of plasma cardiac troponin T (cTnT) concentration over time, and B represents the trend of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration over time. Figure 4 The results of cardiac histological analysis of the stress cardiomyopathy mouse model in Example 1 are shown in Figure A, where Oil Red O staining of cardiac tissue shows the deposition of lipid droplets in the myocardium, and Masson's trichrome staining shows the degree of myocardial interstitial fibrosis. Figure 5 For the stress cardiomyopathy mouse model in Example 1 Fosl1 and Il-6 Results of the temporal dynamics of gene expression, where A represents the qRT-PCR analysis of heart tissue. Fosl1 and Il-6 B represents the mRNA expression level, B represents the FOSL1 protein expression level in cardiac tissue detected by Western blot, and C represents the plasma IL-6 concentration analyzed by ELISA. Figure 6 This is what single-cell spatial transcriptome sequencing revealed in Example 1. Fosl1 (A) and Il-6 (B) Spatial distribution results in myocardial tissue of a mouse model of stress-induced cardiomyopathy; Figure 7 This refers to the ISO stimulation of AC16 human cardiomyocytes before and after Example 1. FOSL1 and IL-6 Changes in mRNA expression levels; Figure 8 This is the detection result of the positive mutual regulation between FOSL1 and IL-6 in AC16 cardiomyocytes in Example 2, where A represents the result after transfecting AC16 cells with FOSL1 overexpression plasmid. IL-6 mRNA levels were significantly elevated, B being the result of FOSL1 expression interference using siFOSL1. IL-6 mRNA levels decreased significantly, with C representing the effect of transfection with an IL-6 overexpression plasmid. FOSL1 mRNA levels increased significantly, D represents the effect of silencing IL-6 with siIL-6. FOSL1 mRNA expression was significantly reduced; Figure 9In Example 3 Fosl1 A diagram illustrating the knockout strategy; Figure 10 Fosl1 in Example 3 + / - mouse heart tissue Fosl1 Verification of expression, where A is cardiac tissue. Fosl1 Results of qRT-PCR analysis of gene expression, B is the result of Western blot analysis of FOSL1 protein expression in cardiac tissue; Figure 11 This is a schematic diagram of the experimental procedure in Example 3; Figure 12 For WT group and Fosl1 in Example 3 + / - The results of cardiac function tests in the mice group are shown in Figures A and B, where A and B represent the time trends of left ventricular ejection fraction and fractional shortening, respectively, and C represents the dynamic trend of plasma NT-proBNP concentration. Figure 13 For WT group and Fosl1 in Example 3 + / - CD68 was observed in the hearts of mice in the group of mice after immunofluorescence staining. + Macrophages (red) and CD11b + Distribution of monocytes (green) (A), and CD68 + (B) and CD11b + (C) Results of quantitative analysis of cell percentage; Figure 14 For WT group and Fosl1 in Example 3 + / - Co-staining of BAX (green) and actin (ACTN2, red) in myocardial tissue of mice (A) and quantification of BAX staining area percentage (B). Figure 15 For WT group and Fosl1 in Example 3 + / - Masson trichrome staining of mice showed the degree of myocardial interstitial fibrosis (A) and the quantitative results of relative fibrosis area (B). Figure 16 The results of cardiac function testing in mice in the NS group and TOC group in Example 4 are shown. A is the experimental flowchart, BC are the time trends of left ventricular ejection fraction and shortening fraction, respectively, and D is the dynamic trend of plasma NT-proBNP concentration. Figure 17 The CD68 is observed in the heart immunofluorescence staining of mice in the NS and TOC groups in Example 4. + Macrophages (red) and CD11b + Distribution of monocytes (green) (A), and CD68 + (B) and CD11b +(C) Results of quantitative analysis of cell percentage; Figure 18 The results of co-staining BAX (green) and actin (ACTN2, red) in the myocardial tissue of mice in the NS group and TOC group in Example 4 are shown in (A) and the quantitative results of the percentage of BAX staining area (B). Figure 19 Masson's trichrome staining of mice in the NS and TOC groups in Example 4 shows the degree of myocardial interstitial fibrosis (A) and the quantitative results of relative fibrosis area (B). Figure labeling: Data is expressed as Mean ± SD. p <0.05、 p <0.01、 p <0.005、 p <0.001 indicates a significant difference. Detailed Implementation

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the terminology used herein is for the purpose of describing particular implementations only and is not intended to limit the invention; the terms “comprising” and “having”, and any variations thereof, in the specification and claims of this invention are intended to cover non-exclusive inclusion.

[0022] To address the lack of specific treatments for stress-induced cardiomyopathy in clinical practice, this invention provides a novel treatment strategy based on the discovery of a direct causal link between the FOSL1-IL-6 signaling circuit and stress-induced cardiomyopathy. This strategy aims to significantly improve cardiac function and pathological damage in stress-induced cardiomyopathy by targeting and inhibiting the FOSL1 or IL-6 / IL-6R signaling pathways.

[0023] FOSL1 and IL-6 form a bidirectional positive feedback regulatory loop in stress cardiomyopathy, specifically manifested as: FOSL1 overexpression upregulation IL-6 Expression, knockdown of FOSL1 inhibition IL-6 Expression, overexpression of IL-6 upregulated FOSL1 Expression, knockdown of IL-6 inhibition FOSL1 Therefore, targeting either the FOSL1 or IL-6 / IL-6R signaling pathways for functional inhibition can achieve similar therapeutic effects.

[0024] Some embodiments of the present invention provide the application of a FOSL1 inhibition strategy in the treatment of stress cardiomyopathy, namely, administering an effective dose of a substance capable of inhibiting FOSL1 to the patient, wherein the substance capable of inhibiting FOSL1 includes, but is not limited to, siRNA, shRNA or antisense oligonucleotides capable of knocking down FOSL1 expression.

[0025] Other embodiments of the present invention provide the application of a strategy to inhibit the IL-6 / IL-6R signaling pathway in the treatment of stress cardiomyopathy, namely, administering an effective dose of a substance capable of inhibiting the IL-6 / IL-6R signaling pathway to the patient, wherein the substance capable of inhibiting the IL-6 / IL-6R signaling pathway includes, but is not limited to, anti-IL-6R monoclonal antibodies (such as tozumab).

[0026] This invention also provides a drug for treating stress-induced cardiomyopathy, which contains at least an active ingredient that inhibits FOSL1 expression. In addition, other active ingredients that can treat stress-induced cardiomyopathy can be added. For example, the active ingredient that inhibits FOSL1 expression can be combined with the active ingredient that inhibits the IL-6 / IL-6R signaling pathway to form a combination drug to improve the therapeutic effect.

[0027] Furthermore, in addition to the aforementioned active ingredients, drugs for treating stress-induced cardiomyopathy may also contain pharmaceutically acceptable excipients. The term "pharmaceuticalally acceptable excipient" refers to pharmaceutical excipients widely used in the pharmaceutical manufacturing industry, including one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0028] The following are some specific embodiments. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be obtained commercially.

[0029] Example 1 This case study explores the relationship between stress-induced cardiomyopathy and stress-induced cardiomyopathy by constructing a stress-induced cardiomyopathy model. Fosl1 and Il-6 The association between gene expression and other factors was investigated through the following experiments: (1) The clinical and pathological features of stress cardiomyopathy in humans were reproduced using a mouse model.

[0030] Stress-induced cardiomyopathy is more common in postmenopausal women; therefore, this study used ovariectomized female mice to establish an animal model of stress-induced cardiomyopathy. Figure 1 As shown, one month after bilateral ovariectomy, female mice were given a single intraperitoneal injection of a high dose of isoproterenol (ISO, 200 mg / kg) to simulate the catecholamine storm common in human stress cardiomyopathy, thereby inducing a stress cardiomyopathy model. Echocardiography, plasma biomarker detection (ELISA), and cardiac histology analysis were performed at different time points (0d, 1d, 3d, 7d).

[0031] Echocardiography was used to continuously monitor cardiac function before injection (day 0) and at 1, 3, and 7 days after injection. The results showed that the stress cardiomyopathy model mice exhibited typical balloon-like dilation of the left ventricular apex and basal contraction within 24 hours. Figure 2 A), and the left ventricular ejection fraction and shortening fraction decreased rapidly (A). Figure 2 B-2C indicates acute systolic dysfunction; simultaneously, there is a significant increase in left ventricular end-diastolic and end-systolic volume (B-2C). Figure 2 (D-2E), consistent with transient myocardial stunning. Notably, cardiac function began to partially recover on day 3 and fully returned to normal on day 7, demonstrating the typical functional reversibility of stress-induced cardiomyopathy in humans.

[0032] ELISA analysis showed that, in the presence of impaired cardiac function, plasma cardiac troponin T and N-terminal pro-B-type natriuretic peptide levels were significantly elevated on day 1, and then gradually returned to normal levels. Figure 3 (A-3B) reflects acute myocardial cell injury.

[0033] Oil Red O staining of cardiac tissue can reveal the deposition of lipid droplets in the myocardium, such as... Figure 4 As shown in Figure A, the lipid droplet area significantly increased on day 1, and decreased to normal levels on days 3 and 7. Masson's trichrome staining can reflect the degree of myocardial interstitial fibrosis, and the results are as follows: Figure 4 As shown in B, fibrosis worsened from day 1, peaking on day 7. The above histopathological analysis revealed different trajectories of metabolic and structural changes: Oil Red O staining showed widespread lipid deposition in the myocardium during the acute phase, which gradually subsided over time. Figure 4 A); while Masson's trichrome staining showed that interstitial fibrosis continued to progress from day 3 to day 7 ( Figure 4 (B) indicates that despite the recovery of cardiac function, myocardial structural remodeling is still underway. This separation between functional recovery and persistent fibrosis may constitute the pathological basis for long-term adverse cardiovascular events, or explain the increased long-term cardiovascular morbidity and mortality in some patients.

[0034] (2) In the stress cardiomyopathy model, FOSL1 and IL-6 were upregulated simultaneously.

[0035] qRT-PCR was used to analyze the cardiac tissue of mice with stress-induced cardiomyopathy. Fosl1 and Il-6 The temporal dynamics of gene expression, the results of which are as follows: Figure 5 As shown in A, the mRNA levels of both patients significantly increased during the acute phase of the disease (day 1), gradually decreased as the disease progressed, and returned to normal levels on day 7, with a highly consistent trend.

[0036] The dynamic changes in FOSL1 protein expression levels and plasma IL-6 concentrations in the heart tissue of stress-induced cardiomyopathy mice over time were further verified by Western blot and ELISA, respectively. The results showed that cardiac FOSL1 protein expression and plasma IL-6 concentrations also exhibited synchronous dynamic changes. Specifically, FOSL1 protein was significantly upregulated on day 1, began to decline on day 3, and basically returned to normal on day 7. Figure 5 B); Plasma IL-6 levels were significantly elevated on day 1, began to decline on day 3, and returned to normal on day 7. Figure 5 C).

[0037] Further analysis using single-cell spatial transcriptome sequencing revealed Fosl1 and Il-6 Spatial distribution in myocardial tissue; results showed: Fosl1 and Il-6 The spatial distribution patterns in myocardial tissue highly overlap, and during the acute phase (day 1), the expression signal is mainly enriched in a specific region of the left ventricular free wall, and its expression hotspots exhibit significant spatial co-localization characteristics. Figure 6 (A-6B). The above results indicate that the synergistic activation of the two in the tissue microenvironment exhibits spatial consistency.

[0038] (3) In cell experiments, FOSL1 and IL-6 were upregulated simultaneously.

[0039] AC16 human cardiomyocytes were stimulated with isoproterenol (ISO, 7.5 mM), and the results were detected by qRT-PCR. FOSL1 and IL-6 Changes in gene expression.

[0040] The results are as follows Figure 7 As shown: After ISO stimulation of AC16 human cardiomyocytes, FOSL1 and IL-6 mRNA expression was significantly upregulated ( Figure 7 This result further confirms that FOSL1 and IL-6 are synergistically induced in cardiomyocytes under stress conditions, and jointly participate in the initiation and amplification of myocardial injury.

[0041] Example 2 Based on the finding that FOSL1 and IL-6 are synergistically upregulated in the cardiac tissue of stress-induced cardiomyopathy mice and in ISO-stimulated human AC16 cardiomyocytes, this case further verifies whether there is a mutual regulatory relationship between FOSL1 and IL-6 in stress-induced cardiomyopathy. The specific experiments and results are as follows: The following functional intervention experiments were performed in AC16 cells: ① AC16 cells were transfected with a FOSL1 overexpression plasmid; ② AC16 cells were interfered with using siFOSL1. FOSL1 Gene expression; ③ Transfecting AC16 cells with IL-6 overexpression plasmid; ④ Silencing AC16 cells with siIL-6 IL-6 Genes. qRT-PCR was used to analyze the pre- and post-intervention levels in each group. FOSL1 and IL-6 mRNA expression levels. Specifically, the sense strand (5'-3) of siFOSL1 is: gcucaucgcaagaguagcatt (SEQ ID NO.1), and the antisense strand (5'-3) is: ugcuacucuugcgaugagctt (SEQ ID NO.2); the sense strand (5'-3) of SiIL-6 is: ggcaaagaaucuagaugcatt (SEQ ID NO.3), and the antisense strand (5'-3) is: ugcaucuagauucuuugcctt (SEQ ID NO.4).

[0042] The results are as follows Figure 8 As shown: Overexpression of FOSL1 significantly upregulated IL-6 mRNA expression ( Figure 8 A), while knocking down FOSL1 significantly inhibited IL-6 Express( Figure 8 B); Conversely, overexpression of IL-6 can significantly enhance... FOSL1 level of expression ( Figure 8 C), while silencing IL-6 leads to FOSL1 downregulation (expression down) Figure 8 D). The above results confirm that there is a bidirectional positive feedback regulatory relationship between FOSL1 and IL-6, which together constitute a molecular loop that amplifies myocardial injury signals.

[0043] Example 3 This case validates the application of FOSL1 knockdown in the treatment of stress cardiomyopathy. The specific experiment and results are as follows: To evaluate the therapeutic potential of FOSL1 in stress-induced cardiomyopathy, this study constructed a systemic... Fosl1 heterozygous deletion mouse (Fosl1) + / - ), Fosl1 Knockout strategies such as Figure 9As shown, operational details can be found in existing techniques and will not be elaborated further here. Fosl1 was detected using qRT-PCR and Western blot, respectively. + / - mouse heart tissue Fosl1 Gene expression and FOSL1 protein expression were analyzed, and the results showed that compared with wild-type (WT) control mice, Fosl1 expression was significantly higher. + / - Mouse baseline Fosl1 mRNA levels were significantly lower in WT mice than in WT mice. Figure 10 A), and Fosl1 + / - Mouse FOSL1 protein expression was significantly downregulated ( Figure 10 B).

[0044] like Figure 11 As shown, female WT mice and Fosl1 mice were compared. + / - One month after bilateral ovariectomy, mice were given a single intraperitoneal injection of ISO to induce a stress-induced cardiomyopathy mouse model (injection dose same as in Example 1), and echocardiography, plasma ELISA and cardiac histology were performed at different time points (0d, 1d, 3d, 7d).

[0045] The results of the cardiac function correlation analysis showed that Fosl1 + / - The left ventricular ejection fraction and shortening fraction of mice on day 1 after ISO stimulation were significantly higher than those of WT mice. Figure 12 A-11B), indicating Fosl1 + / - The cardiac function of the mice in the acute phase was significantly better than that of the WT mice, suggesting a significantly reduced degree of systolic dysfunction; meanwhile, Fosl1 + / - The plasma NT-proBNP level in mice was significantly reduced ( Figure 12 C), reflecting a reduction in ventricular wall tension and heart failure load. This result indicates that, compared to WT mice, Fosl1 + / - The mice exhibited a significant cardioprotective effect.

[0046] Histological analysis further revealed its mechanistic basis: Fosl1 in a specific region of the left ventricular free wall + / - CD68 in mice + Macrophages and CD11b + Monocyte infiltration was significantly reduced ( Figure 13 A-13C), indicating that the local inflammatory response was effectively suppressed; Fosl1 + / - The area of ​​BAX-positive staining in the myocardial tissue of mice was significantly reduced during the acute phase. Figure 14 A-14B), indicating that cardiomyocyte apoptosis was inhibited; in addition, Fosl1 + / - The degree of myocardial interstitial fibrosis in mice was significantly reduced in the later stage (7 days) of stress-induced cardiomyopathy. Figure 15(A-15B) The myocardial structural disorder was relieved.

[0047] The above results collectively confirm that reducing FOSL1 expression can significantly improve cardiac function and tissue damage in stress cardiomyopathy by inhibiting key pathological processes such as inflammation, apoptosis, and fibrosis, thus demonstrating clear therapeutic value.

[0048] Example 4 This case demonstrates the application of substances that target and block the IL-6 signaling pathway in the treatment of stress-induced cardiomyopathy. Specific experiments and results are as follows: To evaluate the feasibility of targeting the IL-6 signaling pathway in the treatment of stress-induced cardiomyopathy, this study used toluizumab (TOC), an FDA-approved humanized monoclonal antibody against the IL-6 receptor, to intervene in an ISO-induced stress-induced cardiomyopathy mouse model. The specific experimental procedure is as follows: Figure 16 As shown in Figure A: One month after bilateral ovariectomy, female mice underwent a single intraperitoneal injection of ISO to induce a stress cardiomyopathy model. Four hours after the onset of stress cardiomyopathy, they were given a single intraperitoneal injection of toluizumab (TOC) or normal saline (NS). Subsequently, echocardiography, plasma biomarker detection, and cardiac histology analysis were performed at different time points (1d, 3d, 7d).

[0049] Regarding cardiac function, the left ventricular ejection fraction and shortening fraction were significantly higher in the TOC-treated group than in the NS control group on day 1 after ISO stimulation, indicating that their cardiac function was significantly better than that of the NS control group in the acute phase of stress cardiomyopathy, that is, their systolic function impairment was significantly inhibited. Figure 16 B-16C). Meanwhile, plasma cTnT levels are significantly reduced during the acute phase of stress-induced cardiomyopathy (B-16C). Figure 16 (D) This suggests that the integrity of the myocardial cell membrane was better maintained. Histological analysis further revealed its mechanism of action: in a specific region of the left ventricular free wall, the TOC treatment group significantly inhibited CD68. + Macrophages and CD11b + Abnormal infiltration of monocytes ( Figure 17 A-17C) demonstrates that IL-6 signaling is a core mediator driving local "inflammatory cytokine storm"; the area of ​​BAX-positive staining in myocardial tissue was significantly reduced ( Figure 18 A-18B indicates that stress-induced cardiomyocyte apoptosis was effectively blocked; in addition, the degree of fibrosis in the TOC treatment group was significantly less than that in the NS control group in the later stages of stress cardiomyopathy (3d, 7d). Figure 19 (A-19B), collagen deposition is significantly reduced.

[0050] The above results indicate that IL-6 is not only a key biomarker for stress-induced cardiomyopathy but also a core effector molecule mediating myocardial injury. Blocking IL-6R with TOC effectively interrupts the IL-6-mediated inflammatory cascade, thereby inhibiting regional inflammatory outbreaks and protecting myocardial structure and function, suggesting that TOC treatment can produce multidimensional cardioprotective effects. Given that TOC is widely used clinically with good safety profiles, this invention provides strong experimental evidence for its "drug repurposing" in acute stress-related diseases such as stress-induced cardiomyopathy, and possesses great potential for rapid translation into clinical trials.

[0051] In summary, this invention reveals for the first time the core role of the FOSL1-IL-6 positive feedback signal axis in the pathogenesis of stress-induced cardiomyopathy, and provides two new and effective treatment strategies based on this mechanism (targeting FOSL1 or IL-6R), laying a theoretical foundation for the development of corresponding drugs for the treatment of stress-induced cardiomyopathy.

[0052] It should be noted that the present invention is not limited to the above-described embodiments. The above embodiments are merely examples, and any embodiments that have the same structure and perform the same effects as the technical concept within the scope of the present invention are included within the scope of the present invention. Furthermore, various modifications that can be conceived by those skilled in the art to the embodiments, and other ways of constructing by combining some of the constituent elements of the embodiments, without departing from the spirit of the present invention, are also included within the scope of the present invention.

Claims

1. The use of a substance targeting the FOSL1-IL-6 signaling circuit in the preparation of a drug for treating stress-induced cardiomyopathy, wherein the substance inhibits FOSL1 or blocks the IL-6 / IL-6R signaling pathway.

2. Use according to claim 1, characterized in that, The substance is an inhibitor of FOSL1, including siRNA, shRNA, or antisense oligonucleotides that can knock down FOSL1 expression.

3. The application according to claim 1, characterized in that, The substance is an inhibitor of the IL-6 / IL-6R signaling pathway, including anti-IL-6R monoclonal antibodies.

4. The application according to claim 1, characterized in that, The drug contains pharmaceutically acceptable excipients.

5. A drug for treating stress-induced cardiomyopathy, characterized in that, It contains at least one active ingredient that inhibits FOSL1 expression.

6. The drug according to claim 5, characterized in that, The active ingredient is siRNA, shRNA, and / or antisense oligonucleotides that knock down FOSL1 expression.

Images