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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 4  |  Page : 142-148

Quantitative analysis of kruppel-like factor 5-related messenger RNA transcripts in ischemic myocardium for discrimination of death causes


Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, Beijing, China

Date of Submission30-Oct-2022
Date of Decision07-Dec-2022
Date of Acceptance08-Dec-2022
Date of Web Publication30-Dec-2022

Correspondence Address:
Prof. Dong Zhao
Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, Collaborative Innovation Center of Judicial Civilization, No. 25, Xitucheng Road, Haidian, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jfsm.jfsm_127_22

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  Abstract 


Background: Accumulated studies have demonstrated that Kruppel-like factor 5 (KLF5), a transcription factor, plays an important role in regulating cell proliferation and tissue remodeling through the expression of its downstream genes. KLF5-related factors are expected to be involved in the healing process after myocardial injury or myocardial ischemic changes, especially for the forensic diagnosis of myocardial ischemic physiopathology. Aim and Objectives: This study aimed to explore the discrimination ability and applicability of KLF5-related factors in SCD caused by MI compared with other causes of death to provide further insights into the forensic diagnosis of myocardial ischemic pathology. Materials and Methods: The relative quantification of F-Box and WD Repeat Domain Containing 7 (FBW7), KLF5, factor-binding protein (FGFBP) 1, and FGFBP2 messenger RNAs (mRNAs) in myocardial tissue samples was performed using real-time fluorescence quantitative reverse transcription polymerase chain reaction. KLF5 and FGFBP1/2 protein levels were examined using immunohistochemistry (IHC). The forensic autopsy cases (27 in total, autopsy within 72 h postmortem) included seven cases of acute myocardial infarction and 10 cases of acute myocardial ischemia. There were 10 cases in the control group, including four cases of traffic injury one case of injury by fall from height, one case of electric death, and four cases of blunt force injury. Results: Characteristic results were found in myocardial samples from three groups of deaths: KLF5 and FGFBP1 mRNA levels were significantly elevated in the infarction and ischemia groups, while FBW7 mRNA levels were significantly decreased. FBW7 is an important ubiquitin ligase that can mediate the degradation of KLF5 protein. In addition, FBW7 and FGFBP2 mRNA levels were decreased in the infarction group compared with the ischemia group. The IHC results were consistent with the observed mRNA expression patterns. Conclusions: Quantitative detection of FBW7, KLF5, FGFBP1, and FGFBP2 mRNA transcripts in myocardial tissues supports the pathophysiological study of myocardial ischemic diseases and provides molecular pathological evidence for forensic discrimination of death causes.

Keywords: F-box and WD 40 repeat domain–containing 7, fibroblast growth factor-binding protein, Kruppel-like factor 5, myocardial ischemia


How to cite this article:
Ma X, Li Y, Xi Y, Su L, Tong Y, Wang C, Yu T, Zhao D. Quantitative analysis of kruppel-like factor 5-related messenger RNA transcripts in ischemic myocardium for discrimination of death causes. J Forensic Sci Med 2022;8:142-8

How to cite this URL:
Ma X, Li Y, Xi Y, Su L, Tong Y, Wang C, Yu T, Zhao D. Quantitative analysis of kruppel-like factor 5-related messenger RNA transcripts in ischemic myocardium for discrimination of death causes. J Forensic Sci Med [serial online] 2022 [cited 2023 Feb 3];8:142-8. Available from: https://www.jfsmonline.com/text.asp?2022/8/4/142/366418


  Introduction Top


Sudden death is defined as an acute and unexpected death caused by a potential disease or acute dysfunction of vital organs. This poses a challenge for clinical diagnosis and therapy decisions, but also for determining the cause of death in forensic medicine practice.[1],[2],[3] According to statistical population data, the incidence of sudden cardiac death (SCD) ranks first among sudden deaths, accounting for approximately 60% to 70% of cases.[4] Among them, SCD caused by myocardial ischemic diseases accounts for the overwhelming majority. Myocardial ischemia, without leading to sudden death, can occur repeatedly, resulting in decreased cardiac function with the formation of new or old lesions, especially under the condition of myocardial infarction (MI). In Europe, America, and China, the morbidity and mortality rates of heart failure (HF) caused by MI are by far the highest compared with other cardiovascular diseases.[5],[6],[7]

Following MI, cardiac tissue remodeling is one of the pathological bases of HF, which is characterized by ventricular dilatation and cardiac dysfunction.[8],[9] Early intervention and prevention can help delay the progression of HF after MI, alleviate the courses of ventricular remodeling and cardiac dysfunction, and may be beneficial to the patient's long-term prognosis. How to reduce the morbidity and mortality of HF is a major issue in the field of cardiovascular disease prevention and treatment. In forensic pathology, there is still a lack of biological markers for effectively diagnosing ischemic myocardial injury.[10],[11] Therefore, there is an urgent need to explore and discover the biological mechanisms and markers related to myocardial ischemia to strengthen potential early pathological diagnosis of death causes. Existing studies have found that Kruppel-like factor 5 (KLF5) and its related genes have potential roles in myocardial ischemia and are expected to be used as biomarkers for forensic pathological diagnosis of related diseases.[12]

In this study, we focused on the important transcription KLF5 and its related genes, seeking to confirm the differential expression levels associated with myocardial ischemia and other causes of death. In addition, our work aimed to identify new biological markers for diagnosing myocardial ischemia. Our previous studies found that F-Box and WD repeat domain containing 7 (FBW7) is an important ubiquitin ligase and elucidated the molecular mechanism of mediating the degradation of KLF5 and other proteins in various human cells.[13],[14],[15],[16],[17],[18] However, the characteristic expression profiles of KLF5-related genes and FBW7 in SCD caused by MI remain unclear. We know that expression of the fibroblast growth factor-binding protein (FGFBP) gene in the KLF5-related signaling pathway has an important role in myocardial ischemic diseases.[19],[20] Therefore, this study adopted practical forensic autopsy cases and quantitatively detected the messenger RNA (mRNA) transcript levels of FBW7, KLF5, FGFBP1, and FGFBP2 in cardiac tissue samples. We aimed to explore the discrimination ability and applicability of these genes in SCD caused by MI compared with other causes of death to provide further insights into the forensic diagnosis of myocardial ischemic pathology.


  Materials and Methods Top


Subjects and samples

Serial forensic autopsy cases at our institution that were within a 72-h postmortem period were examined: a total of 27 cases were included, with 20 males and 7 females ranging in age from 25 to 71-year-old (median, 52) [Table 1]. From routine macromorphological, micropathological, biochemical, and toxicological findings, the cadavers were classified into groups by cause of death, including acute MI (n = 7), acute myocardial ischemia (n = 10), and controls (n = 10). For these groups, clearly accountable cases were collected, with cases involving complications that may have influenced the process of death being excluded. The acute MI and acute myocardial ischemia groups included cases without any morphological or toxicological evidence of the cause of death other than a cardiac attack.[21],[22] The morphological severity of the myocardial injury was examined on the anterior wall of the left ventricle, the posterior wall of the left ventricle, and the right ventricle by h and e (HE) staining microscopical findings. The degree of myocardial ischemia was divided according to the abbreviated injury scale.[23] When the microscopic manifestations were local necrosis, diffuse necrosis, and diffuse eosinophilic changes, the sample was divided into MI group, and others only with local eosinophil infiltration or mild punctate necrosis were identified as myocardial ischemia group samples.[21] In the control group, the individuals died from mechanical violence, such as falls from height, electric death, traffic injury, and blunt force injury. The controls were physically healthy, with no cardiogenic disease. Furthermore, cases with combined causes of death were excluded, as well as cases with a delayed death process. Before collecting the data, everything was explained to the participants and consent was taken. This study has been approved by Ethical Committee, Institute of Evidence Law and Forensic Science, China University of Political Science and Law (Item Number: 2019001, Date: March 8, 2019).
Table 1: Case profiles

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During the autopsy, the myocardial tissue samples were taken from the anterior wall of the left ventricle, the posterior wall of the left ventricle and the right ventricle, then immediately submerged them in 1 mL of RNA stabilization solution (RNAlaterTM, Ambion, Austin, TX, USA) and stored at 4°C for <1 week until RNA extraction. Total RNA was isolated with ISOGEN (Nippon Gene, Toyama) according to the manufacturer's instructions and stored at −80°C until use.[24],[25]

Reverse transcription polymerase chain reaction and relative quantification of messenger RNA

Reverse transcription polymerase chain reaction was performed using the Genstar kit on an ABI PRISM 7500 Sequence Detector (PerkinElmer Applied Biosystems, Foster City, CA, USA). The contents of the amplification mix and thermal cycling conditions were set according to the accessory protocols. Amplification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was performed as an endogenous reference. FBW7, KLF5, FGFBP1, and FGFBP2 mRNA levels were also examined. Primers for FBW7, KLF5, FGFBP1, FGFBP2, and GAPDH mRNA were synthesized as described previously.[26],[27] The relevant primer information is shown in [Table 2]. Following the manufacturer's instructions, the relative quantification of mRNA transcripts was performed using the comparative threshold method.[25]
Table 2: Primer sequence information

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The mRNA expression levels of FBW7, KLF5, FGFBP1, and FGFBP2 are each represented as the ratio of the target gene normalized to GAPDH mRNA levels. Fold change ratios relative to a calibrator sample were then obtained.

Immunohistochemistry of Kruppel-like factor 5 and factor-binding protein in the cardiac tissues

Serial 5-μm thick tissue sections were taken from formalin-fixed paraffin-embedded cardiac tissue specimens. Polyclonal goat anti-KLF5 (AF-3758; R and D Systems, diluted 100-fold) and polyclonal mouse anti-FGFBP (MAB-1593, R and D Systems, diluted 100-fold) antibodies were used with a universal streptavidin/biotin immune-peroxidase detection system (OmniTags kit). Diaminobenzidine20X (DAB) (ZSGB-BIO, China) was used as the chromogen with nuclear counterstaining using hematoxylin. As a negative control to confirm the specificity of immunostaining, 0.9% saline was substituted for the primary antibody.[24]

Statistical analyses

The data are expressed as mean ± standard deviation after testing the normality of data distribution, and SPSSv.24.(IBM, New York, USA) was used for statistical analysis. From the results of the homogeneity of variance test, analysis of variance or Brown-Forsythe test was used for comparisons between groups and a least-significant difference or Tamhane's test was used for multiple comparisons. Student's t-tests were used for pairwise comparisons between the left ventricular anterior wall, left ventricular posterior wall, and right ventricular samples within each group. P < 0.05 was considered statistically significant.


  Results Top


Messenger RNA quantitative analysis in relation to gender, age, and intra-group expression differences

Overall, the cases showed no gender-related or age-related differences in FBW7, KLF5, FGFBP1, or FGFBP2 mRNA levels in cardiac tissues (P > 0.05). The mRNA expression levels of related biomarkers in different parts (the anterior wall of the left ventricle, the posterior wall of the left ventricle, and the right ventricle) of each group (infarction, ischemia, and control) were also compared [Figure 1], with no significant differences found (P > 0.05). Therefore, samples of these three areas were equivalent volume mixed for subsequent statistical analysis.

F-Box and WD repeat domain containing 7, Kruppel-like factor 5, factor-binding protein 1, and factor-binding protein 2 messenger RNA quantification with reference to the cause of death

Compared with the control group, the mRNA expression levels of KLF5 and FGFBP1 in the infarction group were significantly increased. On the contrary, the expression levels of the other mRNAs decreased, especially for FBW7. When comparing the ischemia group with the control group, we found that KLF5 and FGFBP2 mRNA levels significantly increased. In addition, FGFBP1 mRNA levels significantly increased, FBW7 and FGFBP2 mRNA levels significantly decreased in the infarction group compared with the ischemia group [Figure 2].
Figure 1: The t-test of expression difference of mRNAs in different sampling parts between infarction, ischemia and control group. (a) FBW7 mRNA expressions. (b) KLF5 mRNA expressions. (c) FGFBP1 mRNA expressions. (d) FGFBP2 mRNA expressions. ns, P > 0.05. FBW7: F-Box and WD Repeat Domain Containing 7, mRNA: messenger RNA, KLF5: Kruppel-like factor 5, FGFBP: Factor-binding protein

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Figure 2: Each biomarker mRNA expressions in relation to the cause of death. (a) FBW7 mRNA expressions. (b) KLF5 mRNA expressions. (c) FGFBP1 mRNA expressions. (d) FGFBP2 mRNA expressions, ANOVA or Brown Forsythe test indicated the significant contrast: *, P < 0.05; **, P < 0.01; ***, P < 0.001. ANOVA: Analysis of variance, mRNA: messenger RNA

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Immunohistochemistry

In the heart specimens of the MI group, strong positive KLF5 staining was observed in the nuclei of myocardial cells, while the myocardial cell membrane showed weakly positive KLF5 staining. The distribution of KLF5-positive staining in cardiomyocytes was mainly cord-like, with a scattered distribution of dots and flakes. The same findings were observed in the seven samples diagnosed with acute MI. Significantly increased FGFBP protein expression levels were found in the nuclei/cytoplasm of myocardial cells in the MI samples compared with those of the control group [Figure 3].
Figure 3: Results of KLF5 and FGFBP immunohistochemical staining in different group (x400). (A) The expression situation of KLF5. a1: Infarction group, a2: Ischemia group, a3: Control group; (B) The expression situation of FGFBP. b1: Infarction group, b2: Ischemia group, b3: Control group. KLF5: Kruppel-like factor 5, FGFBP: Factor-binding protein

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  Discussion Top


Sudden death from cardiovascular disease is the most common type of sudden death in many countries. With the potentiality, contingency and unexpectedness of the incidence rate of the sudden death from cardiovascular disease is the highest occurring form in adults.[5],[28] Coronary atherosclerotic heart disease is one of the diseases most likely to cause sudden death related to the cardiovascular system.[29] This commonly manifests through the formation of atherosclerotic plaques that are diffusely distributed along the coronary artery. With vascular stenosis, which is an obstruction caused by atherosclerotic plaque protrusion, the coronary blood supply becomes sharply decreased or is interrupted, resulting in severe or persistent myocardial ischemia in this area, or even infarction.[28],[30]

Deaths from myocardial ischemia or infarction are commonly encountered in forensic autopsies.[31] Currently, the forensic pathological diagnosis of sudden death from cardiovascular disease is mainly based on the degree of coronary artery diseases, such as stenosis, and the presence or absence of thrombus, myocardial tissue bleeding, necrosis, organ congestion, and other pathomorphological changes. However, the occurrence of typical myocardial necrotic diseases usually occurs after 5–6 h of complete interruption of myocardial blood supply, and it is often difficult to find specific cardiac pathomorphological findings in autopsy cases with short survival time.[32] For cases without obvious coronary artery or myocardial pathological changes, the diagnosis is mainly based on the exclusion of other causes of death, such as mechanical asphyxia, acute poisoning, or others.[33],[34] In fact, most cases of SCD are difficult to discriminate from certain cases of asphyxia, drowning, and acute poisoning, especially those without significant coronary artery stenosis and myocardial ischemia. In forensic pathology, an expert conclusion of SCD, such as from acute ischemic heart disease or acute coronary heart disease, in cases that lack myocardial ischemic morphological changes can only be obtained after excluding other causes of death. To improve the differential diagnosis of SCD and fully understand the case, solely relying on the macroscopic/microscopic morphological observations after autopsy is not sufficient. Recent advances in molecular pathology techniques have indicated that the quantitative analysis of mRNA expression levels of myocardial ischemia pathway-related genes can significantly supplement traditional macroscopic/microscopic morphological observations.

FBW7 (also known as FBXW7 or CDC 4) is an F-box protein (FBW7, E3 Ubiquitin Protein Ligase), which is an important ubiquitin ligase. In our previous studies, we clarified the molecular mechanism of FBW7-mediated degradation of proteins such as KLF5 in various human cells.[13],[14] FBW7 can assemble the substrate of SCFFBW7 ubiquitin ligase (a complex composed of SKP1, CUL1, and F-box proteins). The FBW7 protein interacts with the Cdc4 phospho-degrons (CPDs) of KLF5 and other substrates through WD40 repeat units, leading to ubiquitination modification and degradation of substrate proteins. KLF5 (also known as BTEB2 and IKLF), belonging to the KLF family, is a transcription factor closely involved in the proliferation, differentiation, and death of a variety of cell types.[16] It has been reported that KLF5 and its related downstream gene FGFBP of the TPA/MAPK signaling pathway play important roles in myocardial ischemic diseases[19] and the activation of fibroblast growth factors (FGFs). FGFs, as regulatory factors of cell proliferation/differentiation in the extracellular matrix, are mostly combined with heparin and require FGFBP to be active.[35] FGFBP gene expression has high tissue specificity and is strictly regulated by different promoter elements. FGFBP-1, FGFBP-2, and FGFBP-3 genes exist in eukaryotes and are evolutionarily distinct, while FGFBPs are highly homologous proteins.[36] KLF5 binds to GC-rich DNA sequences of the FGFBP gene to promote cell proliferation, migration, and survival, alter the cell cycle process, and participate in angiogenesis.[19] Although it is highly expected that the “FBW7-KLF5-FGFBPs” signaling pathway is substantially involved in myocardial ischemic diseases[17] and therefore upholds potential application in forensic pathology, the characteristic expression profiles of KLF5-related genes and FBW7 in myocardial ischemia remain unclear. This study examined practical forensic autopsy cases and quantitatively detected the mRNA transcripts of FBW7, KLF5, FGFBP1, and FGFBP2 in the cardiac tissue samples. We aimed to explore the discrimination ability and applicability of these genes in SCD cases caused by MI compared with other causes of death.

In this study, the mRNA expression levels of FBW7, KLF5, FGFBP1, and FGFBP2 in myocardial tissues were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction, while KLF5 and FGFBP protein expression levels were examined by immunohistochemistry (IHC) staining. To focus on acute dynamic mRNA changes and reduce the postmortem effects on mRNA quantification, this study selected acute death cases and excluded cases with postmortem intervals longer than 72 h. There were no significant expression differences between the left ventricular anterior wall, left ventricular posterior wall, and right ventricular wall for the genes in this study. Therefore, samples of these three areas were mixed to ensure that the sample size of the study was sufficient. Our results showed that FBW7, KLF5, and FGFBP mRNAs had distinct expression patterns between the acute myocardial ischemia/infarction groups and the control group. Decedents in the control group had other causes of death types. These three mRNAs showed potential utility for analyzing the seriousness of myocardial ischemia. KLF5 mRNA expression levels increased significantly after myocardial ischemia/infarction, while FBW7 mRNA expression levels decreased markedly. These findings suggested that these factors are involved in the myocardial ischemia and coronary atherosclerosis processes, consistent with our hypothesis.[17],[37] Under normal physiological conditions, KLF5 is expressed at low levels in the cardiovascular system, but its expression is significantly increased in atherosclerosis and activated vascular smooth muscle. FBW7 expression shows the opposite trend, indicating that both KLF5 and FBW7 may mediate atherosclerosis. Studies have found that pro-atherosclerosis factor oxidized low-density lipoprotein can induce high expression of KLF5, thereby promoting the expression of micro RNA (miRNA)-29a in aortic smooth muscle cells. Subsequently, miRNA-29 can downregulate FBW7 expression to alleviate FBW7-mediated ubiquitination and degradation of KLF5, increase KLF5 stability, and form a positive feedback loop for atherosclerosis.[38] In this study, we analyzed the mRNA expression levels of FGFBP1 and FGFBP2, finding that FGFBP1 mRNA levels were significantly increased after acute MI and FGFBP2 mRNA levels were slightly increased after myocardial ischemia compared with the control group. Some studies have confirmed the important role of FGFBP in epithelial tissue regeneration and wound healing.[20],[35],[36] FGFBP is one of the downstream target genes of KLF5. KLF5 directly binds to the GC box (Sp1 site) of the proximal promoter of FGFBP and positively regulates transcription of FGFBP,[39] both of which participate in the TPA and MAPK pathways to regulate cell transformation and angiogenesis.[19],[40] Therefore, the increased expression of FGFBP during MI may be related to the promotion of neovascularization and restoration of myocardial blood supply. We also found that FGFBP1 mRNA expression levels increased significantly with the aggravation of myocardial ischemia, while those of FGFBP2 decreased. Further research is required to clarify these opposing regulatory mechanisms.

IHC staining results confirmed the protein expression patterns of KLF5 and FGFBP in myocardial tissues, which were consistent with the observed mRNA expression patterns of these genes. In myocardial ischemia/infarction tissue sections, KLF5 and FGFBP displayed different degrees of positive protein expression, while no staining was seen in the control group for these proteins. This again indicates the association of these factors with myocardial ischemia progression and the degree of coronary artery stenosis.[38],[41] Compared with RNA real-time quantitative detection, IHC can be used to evaluate the expression of related genes at the protein level. Therefore, the two methods complement one another and more accurately reflect the considerable role each factor plays in the diagnosis of MI.

In summary, this study suggests that the quantitative analysis of FWB7, KLF5, FGFBP1, and FGFBP2 mRNA expression in myocardial tissues could be applied in the pathophysiological diagnosis of sudden death from cardiovascular disease, especially in patients with MI after coronary stenosis and myocardial ischemia progression. We confirmed that KLF5 and FGFBP can be used as indicators for SCD cases of MI/ischemia, serving as objective and sensitive molecular pathological biomarkers for pathological death cause analysis. Overall, our findings will help achieve better discrimination of causes of death, especially for acute myocardial ischemic pathology.

Acknowledgment

The authors would sincerely like to acknowledge the Key Laboratory of Evidence Science at China University of Political Science and Law for providing a facility to standardize PCR reactions. We also thank Haidong Zhang, Xiaofei E, and Mengzhou Zhang for their valuable advice for the case analysis.

Financial support and sponsorship

This work was supported by the Beijing Natural Science Foundation (grant number 7192121, China), and General Program of National Natural Science Foundation of China (grant number 81971796, China).

Conflicts of interest

There are no conflicts of interest.



 
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