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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 66
| Issue : 5 | Page : 306-312 |
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Paricalcitol improved cardiac hypertrophy and fibrosis through upregulation of fibroblast growth factor-23 and downregulation of transforming growth factor-beta in a rat model of isoproterenol-induced cardiomyopathy
Chieh-Jen Wu1, Yu-He Li2, Hsin-Hung Chen3
1 Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
2 Department of Laboratory Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
3 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| Date of Submission | 20-Mar-2023 |
| Date of Decision | 07-Jun-2023 |
| Date of Acceptance | 14-Jun-2023 |
| Date of Web Publication | 18-Sep-2023 |
Correspondence Address:
Dr. Hsin-Hung Chen
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, No. 386, Dazhong 1st Road, Zuoying Dist., Kaohsiung 813414
Taiwan
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/cjop.CJOP-D-23-00048
Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association between acute cardiomyopathy and low vitamin D levels. Although paricalcitol, a vitamin D receptor (VDR) activator, has demonstrated clinical benefits in patients with advanced kidney disease, its effect on cardiac remodeling in cardiomyopathy is unknown. This study aimed to investigate the relative effects of paricalcitol on cardiomyopathy in rats. Wistar–Kyoto rats were administered vehicle (sham control group) or isoproterenol to induce cardiomyopathy. Rats administered isoproterenol were subsequently treated with paricalcitol (experimental group) or vehicle (isoproterenol group). Picrosirius red and immunofluorescence staining were used to analyze cardiac fibrosis and hypertrophy. Immunohistochemistry staining was used to confirm the molecular mechanisms involved in isoproterenol-induced cardiomyopathy in rats. Injection of paricalcitol could reduce collagen and transforming growth factor-beta 1 (TGF-β1) levels while activating fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor-23 (FGF23) without the help of Klotho, thereby reducing myocardial hypertrophy and fibrosis. As a VDR activator, paricalcitol reduces isoproterenol-induced cardiac fibrosis and hypertrophy by reducing the expression of TGF-β1 and enhancing the expression of VDR, FGFR1, and FGF23.
Keywords: Cardiac fibrosis, cardiomyopathy, fibroblast growth factor-23, isoproterenol, paricalcitol
How to cite this article:
Wu CJ, Li YH, Chen HH. Paricalcitol improved cardiac hypertrophy and fibrosis through upregulation of fibroblast growth factor-23 and downregulation of transforming growth factor-beta in a rat model of isoproterenol-induced cardiomyopathy. Chin J Physiol 2023;66:306-12 |
How to cite this URL:
Wu CJ, Li YH, Chen HH. Paricalcitol improved cardiac hypertrophy and fibrosis through upregulation of fibroblast growth factor-23 and downregulation of transforming growth factor-beta in a rat model of isoproterenol-induced cardiomyopathy. Chin J Physiol [serial online] 2023 [cited 2023 Dec 4];66:306-12. Available from: https://www.cjphysiology.org/text.asp?2023/66/5/306/385989 |
Chieh-Jen Wu and Yu-He Li contributed equally to this work.
| Introduction | |  |
As the global population continues to grow and age, the mortality from cardiovascular disease increases. Cardiovascular disease, which affects the heart and blood vessels, is the leading cause of death worldwide. Ischemic heart disease and myocardial fibrosis are two major contributors to heart failure.[1],[2] Myocardial fibrosis is a significant factor in heart disease-related illness and death. It often occurs after a heart attack but can also be caused by conditions such as high blood pressure, diabetic cardiomyopathy, and idiopathic dilated cardiomyopathy.[3],[4] Isoproterenol can trigger oxidative stress and generate free radicals that severely damage the heart muscle. Many studies have established that isoproterenol can induce myocardial infarction, cardiac remodeling, and heart failure in animals.[5],[6],[7],[8],[9]
In animal studies, paricalcitol reduced isoproterenol-induced myocardial infarction size and improved cardiac function through attenuating oxidative stress, inhibiting apoptosis, and modulating autophagy.[10] Moreover, it reduced myocardial fibrosis and improved diastolic left ventricular dysfunction due to transverse aortic constriction-induced pressure overload in a mouse model.[11] However, the mechanisms of these effects remain unclear. Clinically, paricalcitol is used to treat and prevent primary and secondary hyperparathyroidism due to chronic kidney failure.[12] Chronic kidney disease can lead to secondary hyperparathyroidism and renal osteodystrophy due to phosphate accumulation and decreased calcium ion and vitamin D3 concentrations.[13],[14] Kidney disease commonly coexists with cardiovascular disease,[15] and this significantly increases the mortality rate. Paricalcitol is a vitamin D receptor (VDR) activator that has shown significant clinical effectiveness in the treatment of patients with kidney disease; however, its effects in acute cardiomyopathy remain unclear as few studies have explored the correlation between acute cardiomyopathy and vitamin D. Therefore, this study aimed to investigate the impact of paricalcitol on improving isoproterenol-induced cardiomyopathy in rats.
| Materials and Methods | | |
Animals
We used 8-week-old male Wistar–Kyoto rats weighing approximately 250–350 g. The rats were purchased from the National Science Council Animal Facility (Taipei, Taiwan) and raised at the Animal Center of Kaohsiung Veterans General Hospital (Kaohsiung, Taiwan). Rat food was purchased from Purina (Purina, St. Louis, MO, USA), and rats were randomly given water to drink. All animal care and research procedures were approved by the Research Animal Facility Committee of Kaohsiung Veterans General Hospital (VGHKS 2019-2020-A012, 2021-A017, and 2022-A064).
Cardiomyopathy model induction
We randomly divided the rats into three groups (n = 6 per group). In the first group (sham control group), rats were not injected with isoproterenol but only with a vehicle (saline solution containing 0.1% ascorbic acid). In the second group (isoproterenol group), rats were intraperitoneally injected with isoproterenol (Sigma-Aldrich, St. Louis, MO, USA) at a dose of 2 mg/kg/day for 5 consecutive days to induce heart failure. After 1 week, they were injected with a vehicle (saline solution containing 3.9% propylene glycol and 1.3% ethyl alcohol) three times a week for 3 weeks. In the third group (experimental group), rats were intraperitoneally injected with isoproterenol at a dose of 2 mg/kg/day for 5 consecutive days. After 1 week, they were given an intraperitoneal injection of paricalcitol at a dose of 200 ng/kg, administered three times per week for 3 weeks.
Subsequently, mice were sacrificed and myocardial tissue was harvested. For the analyses, we used 4-μm thick sections of left ventricular tissue. The differences in pathological changes in the heart tissue between the control and experimental groups were analyzed.
Collagen content evaluation
After deparaffinization and washing according to the procedure, the tissue sections were stained using a picrosirius red staining kit (ab245887; Abcam, Cambridge, UK). After staining, the sections were observed and imaged with an Olympus microscope (BX 51) equipped with bright-field, fluorescence, and polarized light. ZEISS ZEN microscopy software (blue edition, Version 2.3, Carl Zeiss Microscopy GmbH, ZEISS Group, Munich, Germany) was used to quantify fluorescence intensity.[16] The polarized light intensity of the images was quantified based on the color threshold. The collagen content was measured using ImageJ (National Institutes of Health, Bethesda, MD, USA).
Immunofluorescent analysis of cardiac hypertrophy
After deparaffinization and washing according to the procedure, the tissue sections were first incubated with phosphate-buffered saline containing 10 mm sodium azide, and subsequently with 1 mg/mL wheat germ agglutinin (WGA). The stained tissue sections were mounted with a coverslip using a mounting medium and photographed using a fluorescence microscope. WGA-positive cells were counted and their surface area was quantified using ImageJ (National Institutes of Health).
Immunohistochemical analysis
After deparaffinization and washing according to the procedure, the tissue sections were cultured in a mixture of 30% H2O2-methanol and then incubated overnight at 4°C in 3% serum with anti-transforming growth factor-beta 1 (TGF-β1; Santa Cruz Biotechnology, sc-146, 1:50), anti-fibroblast growth factor-23 (FGF23; R&D systems, MAB26291, 1:100), anti-FGF receptor 1 (FGFR1; Proteintech, 60325-1-Ig, 1:500), anti-Klotho (Proteintech, 28100-1-AP, 1:50), and anti-VDR (Abcam, ab109234, 1:100). Subsequently, a secondary antibody (1:200; Vector Laboratories, Burlingame, CA, USA) was added and sections were incubated at room temperature for 1 h and cultured for 30 min using the AB Kit (1:100; Vector Laboratories). After washing with DAB solution (Vector Laboratories), cell nuclei were stained with hematoxylin and sealed with a cover slip. Photographs were taken using an optical microscope.
Immunoblotting analysis
We were performed to observe protein expression in left ventricular tissue by immunoblotting analysis. Then, we separated protein extracts using electrophoresis on 12% SDS-PAGE (protein concentration: 10 μg/sample of tissue, according to the bicinchoninic acid protein assay kit from Pierce, Rockford, IL, USA). The membranes were then incubated with primary antibodies diluted in phosphate-buffered saline containing Tween-20 and 5% bovine serum albumin. The primary antibodies used were anti-TGFβ1 (sc-146, Santa Cruz, Rb, 1:1000), anti-FGF23 (LS-C411984, LSBio, Rb, 1:1000), anti-FGFR1 (60325-1-Ig, Proteintech, Ms, 1:1000), anti-Klotho (PA5-21078, Invitrogen, Rb, 1:1000), anti-VDR (C-20) (sc-1008, Santa Cruz, Rb, 1:1000), and mouse anti-beta actin (AC026, ABclonal, Rb, 1:50000).
Statistical analysis
Data are presented as mean ± standard error of the mean. Two-way analysis of variance with Tukey's test was employed to compare the expression of TGF-β1, FGF23, FGFR1, Klotho, and VDR between the experimental and control groups. IBM SPSS Statistics version 17.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. Statistical significance was set at P < 0.05.
| Results | | |
Myocardial infarction leads to accumulation of collagen, resulting in myocardial fibrosis and impaired heart tissue function. In our experiment, isoproterenol injection resulted in increase in collagen levels in the left ventricular tissue under visible light. However, after subsequent injection of paricalcitol, we observed a decrease in collagen levels under light and fluorescence microscopy, as well as under polarized light [Figure 1]a, [Figure 1]b, [Figure 1]c. Our data suggest that paricalcitol reduces the accumulation of collagen and thus reduces myocardial fibrosis. | Figure 1: Paricalcitol reduces isoproterenol-induced myocardial fibrosis and inhibits transforming growth factor-beta 1 (TGF-β1) expression in rats. (a-c) Picrosirius red staining for collagen shows that isoproterenol increases collagen levels causing myocardial fibrosis. After treatment with paricalcitol, the collagen level is decreased, reducing myocardial fibrosis. The left ventricle tissue is seen with collagen fibers of yellowish-orange birefringence by polarizing microscopy. Images are quantified using the count and measure module of ImageJ. Sum areas of total pixels were automatically generated via the count and measure module for the above settings and used to calculate the percentage of total collagen and background for each tissue. (d and e) Isoproterenol induces TGF-β expression. After treatment with paricalcitol, TGF-β1 expression is decreased, reducing the inducer of myocardial fibrosis. Statistical values are presented as mean ± standard error of the mean; n = 9. *P < 0.05 compared to the control group, #P < 0.05 compared to the isoproterenol + paricalcitol (experimental) group.
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During cardiac fibrosis, TGF-β expression increases, with TGF-β1 being the main form present in mammals. Using TGF-β1 immunohistochemical staining, we found increased TGF-β1 concentrations in the isoproterenol group and reduced concentrations in the experimental group [Figure 1]d and [Figure 1]e. This finding indicates that paricalcitol significantly reduced TGF-β1 expression, indicating reduced myocardial fibrosis.
Immunofluorescent staining with WGA for myocardial hypertrophy showed that isoproterenol injection induced myocardial hypertrophy, while paricalcitol injection resulted in improvement in myocardial hypertrophy [Figure 2]a and [Figure 2]b. This result indicates that paricalcitol can reduce isoproterenol-induced myocardial hypertrophy. | Figure 2: Paricalcitol reduces isoproterenol-induced myocardial hypertrophy in rats. (a) Using immunofluorescent staining analysis, heart sections were stained with wheat germ agglutinin. Isoproterenol induced myocardial hypertrophy, while paricalcitol improved myocardial hypertrophy induced by isoproterenol. (b) The area of myocardial hypertrophy was statistically analyzed. Statistical values are presented as mean ± standard error of the mean; n = 9. *P < 0.05 compared to the control group, #P < 0.05 compared to the isoproterenol group.
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We performed immunohistochemical staining analysis to confirm whether paricalcitol can improve the defect of expression of growth factors caused by isoproterenol-induced cardiac fibrosis and myocardial hypertrophy. Isoproterenol injection resulted in decrease in FGF23 expression, whereas subsequent paricalcitol injection significantly restored FGF23 expression [Figure 3]a and [Figure 3]b. In addition, injection of isoproterenol decreased FGFR1 expression, which increased after paricalcitol injection [Figure 3]c and [Figure 3]d. We also investigated the expression of Klotho, an auxiliary factor that can help FGF23 effectively bind to FGFR1. Compared to that in the sham group, the expression of Klotho was significantly decreased after isoproterenol injection but did not significantly increase after paricalcitol injection (experimental group) [Figure 3]e and [Figure 3]f. | Figure 3: Paricalcitol can improve the expression of fibroblast growth factor-23 (FGF23)-fibroblast growth factor receptor-1 (FGFR1)-Klotho suppressed by isoproterenol-induced myocardial lesions. (a and b) Injection of isoproterenol in rats suppressed the expression of FGF23 in the heart. After paricalcitol treatment, FGF23 expression increased and was significantly restored compared to that in the control group. (c and d) Injection of isoproterenol in rats suppressed the expression of FGFR1 in the heart. After paricalcitol treatment, FGFR1 expression increased and was significantly restored compared to that in the control group. (e and f) Injection of isoproterenol in rats suppressed the expression of Klotho in the heart. Paricalcitol treatment did not significantly restore Klotho expression compared to that in the control group. Statistical values are presented as mean ± standard error of the mean; n = 9. *P < 0.05 compared to the control group, #P < 0.05 compared to the isoproterenol group.
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To confirm whether paricalcitol can improve the expression of VDR in cardiac tissue and regulate isoproterenol-induced cardiomyopathy, we studied its effect on cardiac VDR expression using immunohistochemical staining analysis. Isoproterenol injection reduced VDR expression, whereas subsequent paricalcitol injection restored the expression of VDR to the same level as that in the sham group [Figure 4]a and [Figure 4]b. Finally, we also examined the expression of several proteins in left ventricular tissue, including TGF-β1, FGF23, FGFR1, Klotho, and VDR [Figure 5]. Isoproterenol injection reduced the protein expression levels of Klotho, FGF23, FGFR1, and VDR but raised the protein expression level of TGF-β1. Paricalcitol treatment reversed these changes in expression after isoproterenol injection. | Figure 4: Paricalcitol can improve the expression of vitamin D receptor (VDR) suppressed by isoproterenol. (a and b) Injection of isoproterenol in rats caused heart failure and suppressed the expression of VDR. After treatment with paricalcitol, the expression of VDR improved and returned to a level same as that in the control group. Statistical values are presented as mean ± standard error of the mean; n = 9. *P < 0.05 compared to the control group, #P < 0.05 compared to the isoproterenol group.
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 | Figure 5: Paricalcitol improves the protein expression of fibroblast growth factor-23 (FGF23)-fibroblast growth factor receptor-1 (FGFR1)-Klotho and vitamin D receptor (VDR) suppressed by isoproterenol. Quantitative immunoblotting and densitometric analysis demonstrated the expression levels of (a) transforming growth factor-beta 1, (b) FGF23, (c) Klotho, (d) FGFR1, and (e) VDR in rat heart tissue. Values are presented as mean ± standard error of the mean; n = 3. *P < 0.05 compared to the control group, #P < 0.05 compared to the isoproterenol group.
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| Discussion | | |
The major findings of this study are as follows. First, paricalcitol attenuated isoproterenol-induced myocardial fibrosis as indicated by the reduced collagen content and TGF-β1 expression. Second, paricalcitol improved isoproterenol-induced myocardial hypertrophy. Third, paricalcitol ameliorated the inhibition of the FGF23-FGFR1-Klotho endocrine axis and reversed the downregulation of VDR caused by isoproterenol-induced cardiomyopathy.
Many studies have indicated that paricalcitol increases the expression of FGF23 and may exert a potential protective effect against hyperphosphatemia and local increases in calcium and phosphorus concentrations in vessels.[17],[18],[19] In our rat model of isoproterenol-induced cardiomyopathy, paricalcitol could attenuate myocardial hypertrophy and ameliorated left ventricular fibrosis. These effects were due to the increased expression of FGF23, FGFR1, and VDR, as well as the reduced TGF-β expression in the heart.
TGF-β proteins play an important role in many physiological processes, including embryogenesis, cellular development and differentiation, immune system function, inflammatory response, fibrosis, and wound repair.[20],[21],[22] Many studies have shown that TGF-β plays a crucial role in the occurrence and progression of endothelial-to-mesenchymal transition (EndMT).[23],[24],[25] TGF-β1 signaling is regarded as the main inducer of EndMT,[25] whereas FGF-FGFR1 signaling has been demonstrated to downregulate TGF-β signaling and inhibit EndMT.[26] Previous studies have indicated that TGF-β receptor antagonists can inhibit tumor necrosis factor production and reduce cardiac muscle fibrosis in mice. In animal studies, TGF-β1-deficient mice showed improved cardiac fibrosis, indicating that TGF-β may be involved in the pathogenesis of cardiac fibrosis. In contrast, mice overexpressing TGF-β1 exhibited significant cardiac fibrosis.[27],[28],[29] In mouse models of ischemia-reperfusion injury, myocardial ischemia-reperfusion injury triggered a variety of adverse responses to myocardial cell damage, including myocardial hypertrophy, insufficient angiogenesis, and excessive fibrosis.[30],[31],[32] Contrarily, paricalcitol prevented cardiac hypertrophy[33] and fibrosis,[34] and inhibited the development of heart failure in rats via the TGF-β signaling pathway.[35] Similar results were obtained in our study using rats with isoproterenol-induced cardiomyopathy.
Inactivation of FGFR1 and FGFR2 in cardiomyocytes exacerbates the consequences of ischemia-reperfusion injury; therefore, increasing FGFR1 and FGFR2 activity has a cardioprotective effect.[36] Our study found that intraperitoneal injection of a certain dose of isoproterenol can establish a rat model of myocardial hypertrophy and fibrosis. After injection with paricalcitol, myocardial hypertrophy and fibrosis improved and a change was observed in the expression levels of TGF-β1, VDR, FGF23, and FGFR1. These findings indicate that EndMT occurs during the development process of myocardial fibrosis. Isoproterenol injection reduced the expression levels of VDR, Klotho, FGF23, and FGFR1. However, after paricalcitol injection, the expression of VDR, FGF23, and FGFR1 significantly increased. This suggested that paricalcitol can ameliorate myocardial hypertrophy and fibrosis while also exerting a cardioprotective effect. Using paricalcitol to activate VDR can elicit a response from FGF and FGFR1 and has an inhibitory effect on fibrosis. This supports the complex interaction between the vitamin D system and FGFR1-FGF23 in local tissue expression levels. Our experiments have shown that endogenous Klotho expression is reduced in an isoproterenol-induced heart failure model. The cardiac VDR deficiency in heart failure may explain the accelerated aging and fibrosis of these patients' hearts. Our findings also suggest that low levels of VDR in heart failure cannot protect the heart because the reduced expression of FGF23-FGFR1 induces heart failure. We confirmed that paricalcitol induces cardioprotection by increasing cardiac FGF23 expression and binding to FGFR1. Our study can explain the role of cardiac FGF23 in the interaction between FGFR1 and VDR in heart failure. Paricalcitol is currently indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure (stage 5 chronic kidney disease). It is not yet used for the treatment of cardiorenal syndrome, which includes cardiac hypertrophy, fibrosis, and the development of heart failure. Our study findings support the use of paricalcitol in patients with cardiorenal syndrome in the future, with the expectation that it will benefit these patients.
| Conclusion | | |
This study indicated that paricalcitol, as a VDR activator, can improve myocardial fibrosis and hypertrophy caused by isoproterenol-induced cardiac tissue damage by reducing the content of collagen and TGF-β1 expression while increasing the expression of VDR, FGFR1, and the auxiliary factor FGF23.
Acknowledgments
We are grateful to Hui-Yu Chang for the technical assistance and invaluable inputs for this manuscript. Chieh-Jen Wu and Yu-He Li contributed equally to this work.
Author contributions
Chieh-Jen Wu made significant contributions to the conception and design of the work. Yu-He Li helped with acquiring, analyzing, and interpreting data for the work. Hsin-Hung Chen gave final approval for the version to be published and agreed to be accountable for all aspects of the work. This includes ensuring that any questions related to the accuracy or integrity of any part of the work are properly investigated and resolved.
Financial support and sponsorship
This work was supported by the Ministry of Science and Technology of Taiwan (MOST 110-2320-B-075B-001-MY3), Kaohsiung Veterans General Hospital (VGHKS 108-020, VGHKS 109-054, KSVGH 110-012, KSVGH 110-150, KSVGH 111-008, KSVGH 111-152, and KSVGH 112-008), and Zuoying Branch of Kaohsiung Armed Forces General Hospital (KAFGH-ZY-A-109034).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
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