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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 64  |  Issue : 6  |  Page : 281-288

A study of the cardioprotective effect of spermidine: A novel inducer of autophagy


1 Department of Medical Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
3 Department of Clinical Pharmacology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

Date of Submission31-Aug-2021
Date of Decision04-Oct-2021
Date of Acceptance15-Oct-2021
Date of Web Publication27-Dec-2021

Correspondence Address:
Dr. Eman Magdy Omar
Department of Medical Physiology, Faculty of Medicine, Al-Mowassat Hospital, Alexandria University, Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjp.cjp_76_21

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  Abstract 


Acute myocardial infarction (AMI) is an instant death of cardiomyocytes that ends in a large mortality worldwide. Thus, there is a great interest to come up with novel protective approaches for AMI to mount cardiomyocyte survival, enhance postinfarcted cardiac function, and countermand the process of cardiac remodeling. Spermidine has vital roles in vast cellular processes under pathophysiological circumstances. This study aims to enhance our comprehension of the role of autophagy as a possible protective sequel of spermidine supplementation on postinfarction ventricular dysfunction in a rat model of AMI induced by isoproterenol (ISO). Thirty male rats were divided into three groups (control, AMI, and spermidine + AMI). AMI was induced by subcutaneous ISO injections for two consecutive days. Rats were pretreated with spermidine by intraperitoneal injection before induction of AMI. Electrocardiogram (ECG) was recorded in all rats 24 h after the second dose of ISO. Rats were sacrificed after ECG recording, and samples were taken for biochemical assessments. Spermidine intake before induction of AMI in rats significantly attenuated cardiac dysfunction where cardiac enzymes are decreased, and ECG changes induced by ISO are reversed in cardiomyocytes. Spermidine affects the autophagic flux of autophagy-related protein expression (LC3-II, TFEP, and p62). Furthermore, it increased the total antioxidant capacity.

Keywords: Acute myocardial infarction, autophagy, oxidative stress, spermidine


How to cite this article:
Omar EM, Omar RS, Shoela MS, El Sayed NS. A study of the cardioprotective effect of spermidine: A novel inducer of autophagy. Chin J Physiol 2021;64:281-8

How to cite this URL:
Omar EM, Omar RS, Shoela MS, El Sayed NS. A study of the cardioprotective effect of spermidine: A novel inducer of autophagy. Chin J Physiol [serial online] 2021 [cited 2022 May 21];64:281-8. Available from: https://www.cjphysiology.org/text.asp?2021/64/6/281/333802




  Introduction Top


Myocardial infarction is a major public health problem and the leading cause of mortality in both developed and developing countries. Consequently, there is a great concern to come up with novel protective and therapeutic approaches for acute myocardial infarction (AMI). Isoproterenol (ISO) model of rats represents a noninvasive, efficient, reliable model of changes ensuing in the myocardium during AMI. When injected in supramaximal doses,[1] ISO produces tremendously cytotoxic reactive oxygen species (ROS) that enhance membrane phospholipids peroxidation. This brings about marked dysfunction of myocardial membrane and accordingly an infarct-like necrosis of heart muscle.[2]

Spermidine is a naturally occurring polyamine, found in abundance in certain foods, such as rice bran, broccoli, mushrooms, aged cheese, and soybeans.[3] Spermidine has crucial roles in different cellular processes under pathophysiological circumstances.[4] Recent studies highlighted its ability in prolongation of lifespan of many model organisms, including yeast, flies, nematodes, and mice.[5] It is to be mentioned that the longevity-promoting activity of spermidine is associated with its capacity in fostering autophagy.[6]

Autophagy is a crucial process for cells to maintain homeostasis. It cleans the interiors of the cells by forming a double-membraned organelle called autophagosomes. These organelles deliver protein aggregates and aberrant organelles to the lysosomes for degradation.[7] The main stimulants for autophagy are metabolic stress and nutrient deprivation.[8] More than 30 kinds of autophagy-related proteins are documented to be implicated in the process of autophagy.[9] Basal autophagy has been shown to be critical for maintaining the normal function and structure of the heart. However, it was revealed that disturbed autophagy contributes in the pathogenesis and development of heart failure.[10] Autophagy can halt myocardial remodeling, enhance the function of the heart during AMI and delay the progression of AMI to heart failure.[11]

Hence, appropriate evocation of autophagy might be a promising therapeutic target for cardiovascular diseases, together with heart failure. Nevertheless, it is not feasible at the time being to precisely evaluate the autophagic activity in the human heart, though we can benefit from autophagy evaluation techniques in drug discovery and clinical implementation.

The aim of this study was to build up our cognizance of the role of autophagy as possible protective out-turn of spermidine supplementation on postinfarction ventricular dysfunction in a rat model of ISO-induced AMI.


  Materials and Methods Top


Animals and husbandry

Adult male albino Wistar rats, 150–200 g and aged 6–7 weeks, were supplied by the Experimental Animal House in the Physiology Department, Alexandria University. All animals were maintained in a 12 h light/dark cycle and a controlled temperature (24°C ± 1°C) with free access to standard rat chow and water. All experimental procedures were carried out based on the ethical guidelines for the care and use of laboratory animals of Alexandria University. The study was approved by the Faculty of Medicine, Alexandria University Ethics Committee (IRB code 00012098-FWA: No. 00018699; membership in International Council of Laboratory Animal Science organization, ICLAS). All efforts were made to reduce animal suffering and the number of rats needed for the study.

Study design

After acclimatization for 1 week, blood samples were taken to measure cardiac enzymes to exclude any cardiac pathology. Then rats were randomly subdivided into three groups (10 rats each) as follows:

Group I: Control (served as a negative control group). Rats received 1 ml of saline by subcutaneous injection for 2 consecutive days.

Group II: AMI-induced group (served as a positive control group). They received a subcutaneous injection of 85 mg/kg of ISO dissolved in 1 ml of physiological saline for two consecutive days.

Group III: Spermidine + AMI. Rats were pretreated with spermidine (Sigma Chemical, St. Louis, MO, USA) in a dose of 2.5 mg/kg/day for 7 days, by intraperitoneal injection.[12] Then, these rats received subcutaneous injections of ISO, same as Group II rats.

Electrocardiogram (ECG) was done for all rats 24 h after the second dose of ISO or saline. Rats were sacrificed after recording of ECG.

Electrocardiogram

ECG was performed for all rats using a Power Lab system, ECG module (AD Instruments, Transonic Systems Inc., USA).[13] The rats were anesthetized by injection of a mixture of ketamine (80 mg/kg) and xylazine (10 mg/kg). The ECG electrodes were inserted subcutaneously in the rats' limbs when the rats no longer responded to external stimuli. Then the ECG patterns were recorded with standard artifact-free lead II (right forelimb to left hind limb). The Lab Chart analysis software was used to analyze and interpret the data.

Collection of samples

Blood samples were collected from the retro-orbital venous plexus via capillary tube. Serum was separated by centrifugation at 1000 g for 15 min and was assayed for the cardiac enzymes. Additionally, the heart of each rat was removed and rinsed thoroughly with ice-cold phosphate buffer saline (0.01 M, pH 7.4) to remove excess blood. The left ventricle was dissected gently, and the left ventricular tissue was then homogenized, and the homogenates were centrifuged at 2795 g for 20 min. The supernatant was stored at –80°C until assayed for the cardiac parameters.

Biochemical assessment

Detection of serum creatine kinase-MB and lactate dehydrogenase enzymes

Serum creatine kinase-MB (CK-MB) assay was measured colorimetrically (Catalog No. 239003, www.spectrum-diagnostics.com). Serum samples were incubated with a reagent of CK-MB containing the specific antibody to the CK-M subunit that efficiently suppresses the CK-M monomer. The CK-B activity, which was not getting inhibited by the antibody, was determined after a sequence of reaction, by measuring the rate of change in absorbance measured at 340 nm.[14]

Serum lactate dehydrogenase (LDH) assay was measured colorimetrically (Catalog No. 11580, BioSystems). LD catalyzes the conversion of pyruvate compound to L-lactate while the reduced form of nicotinamide adenine dinucleotide is oxidized. The rate of oxidation process is proportional to the activity of LD. This activity is accurately monitored by measuring the decrease in absorbance at 340 nm.[15]

Detection of cardiac total antioxidant capacity

Total antioxidant capacity (TAC) in heart tissue was measured colorimetrically according to the assay kit protocol (Catalog No. TA 25 13, BioDiagnostics).[16]

Detection of cardiac autophagy-related proteins expression by western blot

Western blot was used to quantify LC3-II, p62, and transcription factor EB (TFEB) protein expression in cardiac tissues. After homogenization of cardiac tissues, and the tissue lysate was prepared by adding radioimmunoprecipitation cell lysis buffer (Catalog No. AR0105, [email protected], web: http://www.bosterbio.com), Tris (pH 8.0), and protease inhibitor (Catalog No. AR1182, web: http://www.bosterbio.com). The lysates were assayed for total protein concentration by Lowry method[17] and stored until analysis. After protein electrophoresis, protein transfer from sodium dodecyl sulfate-polyacrylamide gel onto nitrocellulose membrane was performed by electroblotting. Following transfer, bands were detected using Polyclonal Anti-LC3B Antibody (Catalog No. PA5-30598, Thermo Fischer), Anti-SQSTM1/P62 Polyclonal Antibody (Catalog No. PA5-20839, Thermo Fischer), Anti-TFEB Polyclonal Antibody (Catalog No. PA5-75572, Thermo Fischer), and Anti-Beta Actin (Catalog No. PA1-16889, Thermo Fischer). Next, the membranes were incubated with the rabbit IgG DAB Chromogenic Reagent Kit (Catalog No. SA2020, http://www.bosterbio.com). Protein relative band densities ratio were assessed using Image J software system, and protein expression was normalized against control and β-actin.

Statistical analysis

All data were expressed as mean ± standard deviation. Statistical analyses were performed with IBM SPSS statistics, version 22.0 (IBM Inc., Armonk, NY, USA). The normality of data distribution was tested with the Shapiro–Wilk test. One-way analysis of variance was applied for statistical analysis, followed when significant by least significant difference for pairwise comparisons. Pearson correlations were used to test for correlations between different variables as indicated. A probability of P < 0.05 is considered statistically significant.


  Results Top


Electrocardiogram

Heart rate

ISO injection in rats caused a significant increase in heart rate (HR) in both AMI groups compared to the control group. However, spermidine restored the HR, as evidenced by a significant decrease in HR in spermidine-treated rats compared to the AMI group with P < 0.001.

R-R, QRS and QT intervals and ST segment

The AMI group showed a significant attenuation of the duration of both RR and QRS intervals; however, a significant prolongation of the QT interval was demonstrated in comparison to the control group. ST segment elevation is an important sign of AMI. In the current study, it was revealed that there is a significant elevation of the ST segment compared to the control rats.

Pretreatment with spermidine significantly restored the RR interval compared to the AMI group. It is notable that this restoration was complete to reach the normal duration, as there was no significant difference compared to the control group with P < 0.001. Spermidine supplementation also caused normalization of QRS interval compared to the AMI group. However, this was not complete, as its duration was significantly shorter than the control group with P < 0.001. Furthermore, spermidine treatment significantly shortened QT interval compared to the AMI group. This change was not sufficient to bring the QT interval back to the normal values as there was still a significant difference in relation to the control group with P < 0.001. ST segment height was significantly decreased with spermidine compared to the untreated group, yet there was no significant difference in comparison to the control group with P < 0.05 [Table 1] and [Figure 1].
Table 1: Electrocardiogram curve analysis in the different studied groups

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Figure 1: A representative of the electrocardiogram of all studied groups. Control (a), acute myocardial infarction (b), spermidine + acute myocardial infarction (c).

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Biochemical assessment

Serum creatine kinase-MB and lactate dehydrogenase enzymes

ISO injection resulted in a significant increase of both serum cardiac enzymes in AMI group and the spermidine + AMI group in comparison to the control group. However, pretreatment with spermidine caused a significant reduction of CK-MB and LDH in comparison to the untreated group (P < 0.001) [Figure 2]a and [Figure 2]b.
Figure 2: Effect of spermidine supplementation on serum creatine kinase-MB (a), serum lactate dehydrogenase (b), and cardiac total antioxidant capacity (c) in the different studied groups. Data are presented as means ± standard deviation using one-way analysis of variance test (n = 10). aSignificant versus control group, bsignificant versus acute myocardial infarction group, P < 0.001.

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Cardiac total antioxidant capacity

The AMI group showed a significant decrease in TAC compared to the control group; this finding is expected due to cytotoxic effects of ISO. However, spermidine supplementation caused a significant increase in TAC compared to the other groups (P < 0.001) [Figure 2]c.

Cardiac expression levels of autophagy-related proteins by western blot analysis

Western blot was used to detect expression levels of LC3-II, p62, and TFEP proteins. Expression levels of LC3-II and p62 proteins were significantly higher in the AMI group (P < 0.001) than the control group. On the other hand, spermidine supplementation caused a significant increase in LC3-II and TFEP protein expression levels while p62 protein expression decreased significantly compared to the untreated AMI group (P < 0.001) [Figure 3]. Correlations between biochemical markers are presented in [Figure 4].
Figure 3: Effect of spermidine supplementation on LC3-II (a), p62 (b), and transcription factor EB (c) protein expression in cardiac tissue in the different studied groups. Representative immunoblot for the expression of cardiac LC3-II, p62, and transcription factor EB (d). Data are presented as means ± standard deviation using one-way analysis of variance test (n = 10). aSignificant versus control group, bsignificant versus acute myocardial infarction group, P < 0.001.

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Figure 4: Correlations between cardiac expression of LC3-II with transcription factor EB (a) and cardiac total antioxidant capacity with expression of LC3-II (b), p62 (c), transcription factor EB (d) in heart tissue, and serum creatine kinase-MB (e) in the different studied groups (n = 30). Cardiac LC3-II is positively correlated with transcription factor EB (a), cardiac total antioxidant capacity is positively correlated with LC3-II (b), p62 (c), and transcription factor EB (d) and is negatively correlated with serum creatine kinase-MB (e).

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  Discussion Top


AMI is an instant death of cardiomyocytes ending in a substantial mortality worldwide. In order to attenuate MI, strategies have to be undertaken to escalate cardiomyocyte survival, enhance postinfarcted cardiac function, and countermand the process of cardiac remodeling.[18] Autophagy has been supposed to be a novel cell death process implying in the pathophysiological mechanism of AMI. Modulation of autophagy can be considered as a hopeful treatment modality for AMI.[19] Accordingly, in the present study, we investigated the potential benefits of spermidine in reversing the ECG changes associating the occurrence of AMI and decreasing the cardiac enzymes as well. In addition, we explained some of the underlying mechanisms that brought about this outcome, including induction of autophagy and its antioxidant properties.

AMI was induced in the current study by injection of toxic concentration of ISO for 2 consecutive days.[20] ISO is a β-adrenergic agonist drug which exaggerates the HR, potentiates myocardial Ca2+ influx, augments cardiac work, and rises myocardial oxygen demand, causing serious oxidative stress in the myocardium and subsequently infarct-like necrosis of the heart muscle.[21] Moreover, it undergoes autoxidation, releasing highly cytotoxic ROS in the myocardium resulting in contractile dysfunction and cardiomyocytes apoptosis.[22]

Successful induction of the MI model was ascertained by increased levels of serum cardiac enzymes: CK-MB, and LDH. The release of these enzymes from the heart is deemed as a crucial sign of myocardial injury.[23] This could be due to the direct damage of cytotoxic agent on the sarcolemma causing it leaky or secondary to peroxidation of cardiac membrane lipids with leakage of the enzymes from cardiac myocytes.[24] In addition, electrocardiogram recording at the end of the study revealed a significant shortening of RR and QRS intervals duration, prolongation of QT interval, and ST segment elevation. The attenuation of RR interval signifies myocardial edema and disturbance of cell membrane integrity. The QRS interval characterizes the total duration of ventricular depolarization. Its alteration reflects dysfunction of the heart. The QT interval represents the electric systole period, and it reflects the integrity of the myocardium.[25] Its prolongation is associated with cardiac vagal dysfunction and points to abnormal potential of the heart such as arrhythmias, cardiac dysfunction, and sudden cardiac collapse.[26] The ST segment elevation denotes a potential difference between the ischemic and nonischemic zones and subsequent disturbance of cell membrane function. The alterations of ECG pattern in MI induced by ISO have already been described by other researchers.[24],[27]

The protective role of spermidine as an effective treatment for reversing or minimizing the sequels of myocardial injury was mentioned by other researchers, but the actual mechanism has not been elicited.[12] Thus, it was worthwhile to investigate the underlying mechanisms that give rise to the cardioprotective effects of spermidine supplementation. In the present work, treatment with spermidine for 7 days, prior to induction of myocardial infarction, significantly reduced cardiac enzymes and attenuated the ECG changes that issued in AMI in comparison to the nontreated group.

It is well-known that activation of autophagy may be considered as a hopeful approach for protection against the dreadful consequences of AMI. Autophagic flux is a dynamic multistep process that entails the formation of autophagosomes that fuse with lysosomes and eventually degrade.[28] Autophagosomes engulf the cargoes fated for degradation, aided sometimes by autophagy receptors. LC3-II is situated on the membrane of autophagosome and is considered a marker of autophagosome formation in experimental studies.[29] The autophagy receptor proteins have a common domain organization which has a ubiquitin-binding domain, in addition to an LC3-interacting region.[30] This organization allows autophagy receptors to act as bridging molecules to recognize the degradation signal on the autophagic cargo, and to bind LC3 on the growing autophagosomal membrane as well. The most broadly studied autophagy receptor reported to play a chief role in autophagy is p62/SQSTM-1 (sequestosome-1).[31] The intracellular level of p62 is dependent on transcriptional regulation and posttranslational autophagic degradation.[32]

In our study, the expression of both autophagy-related protein LC3-II and the autophagy substrate p62 was increased in AMI compared with the control group. As p62 molecules are themselves autophagy substrates, their aggregation may point out to autophagy dysfunction of which in turn may have led to decreased recruitment of ubiquitinated p62 which hooked up to the cargo molecules to be degraded.[31] On the other hand, Spermidine supplementation increased the expression of LC3-II while decreased that of p62 compared to the MI rats. This may be attributed to activation of autophagy where LC3-I gets lapidated forming LC3-II, which ends up in the recruitment of ubiquitinated p62-cargo complex; the latter is then engulfed into the growing autophagosomes and delivered to lysosomes for degradation leading to decreased levels of p62.[31] These findings may draw attention to the role of spermidine in enhancement and activation of autophagy pathways. It is also worth mentioning that p62 has a positive regulatory effect on mTORC1, so reducing p62 levels in cardiomyocytes, via spermidine intake, could aid potentiation of autophagic flux.[32]

Consistent with our results, it was reported that LC3-II and p62 were elevated in AMI model induced by left anterior descending artery ligation and the administration of autophagy activator (rapamycin) caused a significant increase of LC3-II expression and decreased p62 levels.[33] In line with our findings, researchers identified up‐regulation of LC3-II expression, and decreased p62 expression in a rat model of MI induced by the left anterior descending artery permanent ligation and treated post-MI with spermidine for 4 weeks, suggesting that spermidine potently augmented autophagic flux in post‐MI rats.[28]

TFEB is one of the microphthalmia families of basic helix-loop-helix–leucine-zipper transcription factors (MiT family). TFEB is considered a master controller of the autophagy pathway by driving the expression of autophagy and lysosomal genes.[34] TFEB transfers to the nucleus and controls hundreds of genes including coordinated lysosomal expression and regulatory (CLEAR) network. Those genes are engaged in autophagosomes genesis (such as LAMP-1, VPS11), formation and elongation of the vesicle (such as MAP1 LC3), and recognition and degradation of cargo (such as p62).[35] It was demonstrated that TFEB is necessary for maintaining autophagic-lysosomal pathway (ALP) activity in cardiomyocytes and forced expression of TFEB is sufficient to help facilitation of ALP activity, thus protecting against proteotoxicity induced by misfolded protein. Additionally, it was reported that TFEB activation in macrophages attenuated post myocardial infarction remodeling and ventricular dysfunction. Moreover, it reduced aggregates of pro-inflammatory macrophages, and decreased levels of myocardial interleukin-1 beta.[36] Hence, we suggested that enhancing TFEB activation should be investigated as a therapeutic strategy to attenuate the cardiac stress which is involved in cardiac dysfunction in MI.

In our model, pretreatment with spermidine induced a significant increase in cardiac expression of TFEB compared to both MI and control groups. This underlines a stimulatory effect of spermidine on TFEB which ultimately helps the activation of autophagy axis. This aforementioned conclusion was confirmed by the positive correlation that was identified between the autophagy marker LC3-II and TFEB. These results are in agreement with Zhang et al., who demonstrated that spermidine depletion reduced TFEB protein.[37] These findings may reveal a preventive effect of spermidine on the replacement fibrosis that issues after myocardial infarction through induction of TFEB protein. It is noteworthy that spermidine was reported to have a role in treating lung fibrosis,[38] so further investigations are needed to explore if it takes a part in reversing myocardial fibrosis besides preventing it.

It is agreed that dysregulation of ROS leads to oxidative damage.[39] After the occurrence of MI, oxidative stress and inflammatory responses appeared to cause myocardial injury,[40] so suppression of oxidative damage and inflammation may attenuate cardiac dysfunction following MI. Spermidine carries three positive charges, which function as scavengers for free oxygen radicals and protect nucleic acids and other cellular components from oxidative damage.[41] In the present study, TAC was significantly reduced in AMI compared to the control group. However, pretreatment with spermidine increased the TAC significantly in comparison to the untreated MI group. This finding was in agreement with other researchers[28] who found that spermidine significantly inhibited oxidative stress and reduced the levels of the inflammatory cytokines following MI.

Both autophagy and ROS have pathological or adaptive functions within cardiomyocytes. ROS and autophagy meet up with one another via both transcriptional and posttranslational events.[39] This crosstalk was conspicuous by the positive correlation between cardiac LC3-II expression and TAC outlined in the current study. The negative correlation between cardiac TAC and p62 expression within the cardiac tissue as well as the positive correlation between TFEB expression and cardiac TAC provides further support for the link between autophagy and oxidative stress. Additionally, it should be recalled that we reported a negative correlation between TAC and cardiac enzymes. This above-mentioned communication augments the cardioprotective effect of spermidine in acute MI and reveals some of the mechanisms underlying this protective role.

Blocking the action of autophagy-related protein expression (LC3-II, TFEP, and p62) using specific antibody may provide better apprehension to their exact regulatory mechanism. Unfortunately, this was not evaluated in this study. Thus, we recommend these investigations in further studies to give more detailed assessment of spermidine role in autophagy regulation.


  Conclusion Top


This study emphasized a prophylactic cardioprotective role for spermidine, where its intake enhanced cardiomyocytes survival and decreased its dysfunction post MI. These effects were engendered through its role in the induction of autophagy pathway by way of over-expression of TFEB, and its antioxidative effect as well. Hence, intake of spermidine may have a promising role to prevent or minimize the fatal consequences of AMI.

Acknowledgments

The authors thank the Physiology Department, Faculty of Medicine, for providing the study animals and supporting their housing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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This article has been cited by
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Frontiers in Network Physiology. 2022; 2
[Pubmed] | [DOI]



 

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