Abstract
OBJECTIVES:
The development and progression of chronic heart failure (CHF), hypertrophy, and remodeling strongly correlate with myocardial inflammation and oxidative stress. S-adenosylmethionine (SAMe), available as a dietary supplement, exerts anti-inflammatory and antioxidant effects. Previous reports show that by regulating angiogenesis and fibrosis, S-adenosyl-L-methionine improves ventricular remodeling. The study objectives were to investigate the cardioprotective effect of SAMe in isoproterenol (ISO)-induced CHF and explore the anti-inflammatory and antioxidant properties of SAMe in this model.
METHODOLOGY:
After animal ethics permission, CHF was induced using ISO of 10 mg/kg for 14 consecutive days in 24 Wistar rats. There were four groups of six rats in each group: Sham Control, Disease Control (DC), ISO + SAMe 100 mg, and ISO + SAMe 200 mg. The variables assessed were heart to body weight ratio (HW/BW mg/g), bio-distribution of Flourine 18-Fluorodeoxyglucose (18F-FDG) in heart tissue, tumor necrosis factor-α (TNF-α) and glutathione (GSH) levels in heart tissue, histopathology, and positron emission tomography imaging.
RESULTS:
SAMe in ISO-induced CHF animals showed a significant decrease in the HW/BW compared to DC group (P < 0.001). 18F-FDG uptake was significantly reduced by SAMe in CHF-induced rats compared to DC rats for both doses (P < 0.001). SAMe showed significantly better values of both TNF-α and GSH than the DC group in both doses (P < 0.001). SAMe in both doses showed multifocal necrosis with scarring and minimal inflammatory cells.
CONCLUSION:
SAMe exerts a cardioprotective effect on ISO-induced CHF in rats because of its antioxidant and anti-inflammatory properties.
Keywords: Biodistribution, flourine 18-fluorodeoxyglucose uptake, glutathione (γ-glutamylcysteinyl glycine), heart to body weight ratio, tumor necrosis factor-α
Introduction
Diseases affecting the heart are the most common cause of morbidity and mortality across the world. Chronic heart failure (CHF) is defined as the inability to pump blood due to structural and functional changes in the heart.[1] According to an INDUS study from 2016, the prevalence of CHF in India was around 1.2/1000 people.[2]
Increasing research has shown that the inflammation pathway is one of the important major contributing pathways in the pathophysiology of CHF.[3] The overexpression of pro-inflammatory cytokines such as C-reactive protein, interleukin (IL) 1 and 6, and tumor necrosis factor-α (TNF-α) are often seen in patients with CHF. These cytokines cause cardiac remodeling, myocardial apoptosis, and fibrosis. The severity of CHF is positively associated with these myocardial changes.[4]
The development and progression of CHF, hypertrophy, and remodeling strongly correlate with myocardial oxidative stress.[5] In CHF, a drop in glutathione (GSH) is a sign of ongoing oxidative stress. A study by Hughes et al. found that the New York Heart Association (NYHA) functional class of CHF increases as oxidative stress levels increase. This finding emphasizes the potential importance of approaches to arrest disease progression by reducing oxidative stress.[6]
Although the treatment of CHF has advanced over the past 20 years and the prognosis has improved, overall morbidity, mortality, and readmission rates are still high. There is a need to target new pathological pathways. Thus, a molecule with anti-inflammatory and antioxidant properties could represent a new approach to treating CHF. A new drug that lacks the side effects of the currently available class/drugs would also show promise.[7]
S-adenosylmethionine (SAMe) is required as a methyl donor for cell transmethylation reactions and is central to regulating many biological processes. A cohort study by Liu et al. found an inverse relationship between plasma SAMe levels and mortality risk associated with cardiovascular disease.[8] This study hypothesized that low levels of SAMe are associated with low levels of GSH, a protective antioxidant enzyme that increases the risk of CHF.[8] SAMe is available as a dietary supplement and is indicated for depression, osteoarthritis, and liver disease.[9,10] SAMe exerts analgesic, anti-inflammatory, and antioxidant effects. Yuanchen et al. have reported that SAMe improves the heart structure and function in rats by inhibiting ventricular remodeling after myocardial infarction. However, there is no literature regarding the role of SAMe in CHF experimental models.[11] Therefore, this study assessed the cardioprotective role of SAMe using two doses, 100 mg/kg and 200 mg/kg, in isoproterenol (ISO)-induced CHF in rats.[12,13] The study also explored the anti-inflammatory and antioxidant properties of SAMe in this model.
Methodology
After receiving Institutional Animal Ethics Committee approval ((IAEC/GSMC/04/2020), the study was conducted according to the CPCSEA guidelines. Animals bred at random at the Institute’s Center for Animal Studies were used. Rats were kept in a room with a temperature of 18°C–29°C, 30%–70% humidity, and a 12 h light-dark cycle. They were housed in stainless steel grated polypropylene cages with provision for constant access to pelleted feed and filtered water. Husk was used as the bedding of the cages.
Study drugs/chemicals and doses
ISO, an inducing agent, was purchased from Krishgen Biosystem (5 mg/mL in PBS) and administered subcutaneously. S-adenosyl methionine (SAM-e), a study drug powder, was purchased from Bangalore Sales Limited, India. The powder was dissolved in DW to prepare a 5 mg/mL solution. SAMe (5 mg/mL in DW) was administered through an 18G rat feeding tube. 24 Wistar rats of either sex, aged 6–8 weeks and weighing 180–220 g, were used in this study. Rats were assigned to their respective study group randomly. There were four groups, with six rats in each group.
Group 1: Sham control (SC): Saline in equal volume as ISO by subcutaneous injection (1–2 mL) followed by saline in equal volume as SAMe (oral) (5–10 mL) for 14 days.
Group 2: Disease control (DC): ISO 10 mg/kg/day by subcutaneous injection for 14 days.
Group 3: ISO + SAMe 100: ISO 10 mg/kg by subcutaneous injection followed by SAMe 100 mg/kg orally for 14 days.
Group 4: ISO + SAMe 200: ISO 10 mg/kg by subcutaneous injection followed by SAMe 200 mg/kg orally for 14 days.
Parameter assessed
Heart weight to body weight ratio (mg/g)
On day 15, the body weights of the rats were recorded. Rats were killed by the administration of a high dose of sodium pentobarbitone (50 mg/kg). After opening the chest, the heart was removed, and the atria, aorta, and fatty tissue were separated from the heart. The heart was weighed. The heart weight to body weight ratio (HW/BW mg/g) was calculated.[14]
Biodistribution of the whole heart for flourine 18-fluorodeoxyglucose uptake using gamma scanner followed by ex vivo positron emission tomography scan imaging:
Biodistribution of flourine 18-fluorodeoxyglucose in the whole heart
For biodistribution, each rat was administered Flourine 18-Fluorodeoxyglucose (18F-FDG) by tail vein injection. The rats were kept under anesthesia (isoflurane) during the intravenous administration. The 18F-FDG (50–60 Ci/75-100 L) was injected through the tail vein of Wistar rats.[15] After opening the thorax, the heart was removed. The radioactivity present in the heart was measured using a gamma scanner (1240 GSPEC-USB, Para Electronics, Mumbai, India). The 18F-FDG uptake per gram in each heart was calculated as percent heart uptake. The gamma counts provided by the gamma scanner were converted to percent radioactivity per gram of tissue (% radioactivity/g).
Ex vivo radioimaging by positron emission tomography-scan[16,17]
Hearts were placed on a positron emission tomography (PET) scanner bed, and the scan was performed for 5 min/30 s per frame. The images were recorded using a micro-PET imaging system (β-Eye, Bioemtech Greece) for all rats of different groups.
The heart was divided into two parts by a coronal incision in the middle part of the heart. The upper part consisted of the atria, the lower part consisted of the right and left ventricles, and some parts of the atria. At the same time, the inferior part consisted of the inferior part of the right ventricle, the left ventricle, and the ventricle’s apex. The upper part of the heart was used for the biochemical analysis, i.e. TNF-α and GSH, and the lower part was used for histopathology.
Estimation of cardiac tumor necrosis factor-α[18] and glutathione[19] levels
To estimate GSH and TNF-α, the upper part of the heart (approximately 100 mg) was homogenized in ice-cold PBS (pH-7.4) in a ratio of 1:9 (w/v) and centrifuged at 3000 rpm for 10 min. The supernatant was transferred to another tube and stored at -80°C. The supernatant was thawed and brought to the room temperature for performing the ELISA. The ELISA for GSH and TNF-α was performed as per the manufacturer’s instructions. The levels of TNF-α were expressed as picogram/100 mg of heart tissue and GSH levels as μg/100 mg of heart tissue.
Histopathology[20]
The coronal sections from the apex and lower part of the heart were used for histopathology. These sections were immediately immersed in 10% neutral-buffered formalin. The heart tissue was processed to prepare histopathology slides. Hematoxylin and eosin-stained slides were examined by a veterinary pathologist. The following grading was used as proposed by a veterinary pathologist for the histopathological assessment: Distribution of lesions was noted as focal, multifocal, and diffuse. The severity of lesions was recorded as minimal, mild, moderate, and marked.
Statistical analysis
The study data were expressed as mean (+/−) standard deviation and analyzed using GraphPad InStat version 3.06 (GraphPad Software Inc.,California). Repeated-measures ANOVA followed by post hoc Tukey test was used for all the variables except histopathology. The grading system was used for histopathology, as given by veterinary histopathologists. The level of significance for all variables was P < 0.05.
Results
There was mortality of 1 rat each (total = 2) in ISO + SAMe groups. Hence, the results presented are with five animals for ISO + SAMe groups. Meanwhile, for SC and DC, the results presented were six animals per group.
Heart weight to body weight ratio
There was a significant increase in the heart to body weight ratio in ISO-induced DC animals compared to SC (8.27 ± 0.42 vs. 3.43 ± 0.78, P < 0.001). In ISO-induced CHF rats receiving SAMe, the heart to body weight ratio was reduced compared to the DC group (P < 0.001) [Figure 1].
Figure 1.
Graph showing heart to body weight ratio in percentage. Results expressed as Mean±SD, SC and DC:n=6, ISO+SAMe:n=5, *P<0.001 compared to sham control (SC), #P<0.001 compared to disease control (DC) (Isoproterenol), using one-way ANOVA followed post hoc Tukey’s test
Biodistribution of whole heart for 18F-FDG uptake using gamma scanner followed by Ex vivo PET scan imaging
There was a significant increase in 18F-FDG uptake in disease control rats compared to sham controls (20.45±1.602 versus 4.843±2.032, P<0.001). 18F-FDG uptake was significantly reduced by SAMe in CHF-induced rats compared to disease control rats for both doses (P<0.001). The radio uptake in PET images correlates with the distribution as seen by the gamma scanner [Figures 2 and 3].
Figure 2.
Graph showing Biodistribution of 18 F FDG in heart tissue. Results expressed as Mean±SD, SC and DC:n=6, ISO+SAMe:n=5,*p<0.001 compared to sham control (SC), #p<0.001 compared to disease control (DC) (Isoproterenol), using one-way ANOVA followed by post hoc Tukey’s test
Figure 3.
PET scan images (a-d) showing Radiouptake of 18 F FDG in heart tissue. Image a: Sham control, Image b: Disease control, Image c: ISO+SAM100mg, Image d: ISO+SAM200mg
Cardiac tumor necrosis factor-α and glutathione levels
There was a significant increase in inflammatory marker TNF-α (picogram/100 mg of heart tissue) (680.73 ± 14.48 vs. 259.33 ± 2.16, P < 0.001) and a significant decrease in antioxidant marker GSH (μg/100 mg of heart tissue) (321.28 ± 14.383 vs. 549.42 ± 2.054, P < 0.001) in the DC group compared to the SC group. Both biomarkers showed significant improvement in their levels for SAMe in both doses, compared to the DC group (P < 0.001) [Figures 4 and 5].
Figure 4.
Levels of TNF-α in heart tissue. Results expressed as Mean±SD, SC and DC: n=6, ISO+SAMe:n=5, *P<0.001 compared to sham control (SC), #P<0.001 compared to disease control (DC) (Isoproterenol), using one-way ANOVA followed by post hoc Tukey’s test
Figure 5.
Levels of GSH in heart tissue. Results expressed as Mean±SD, SC and DC: n=6, ISO+SAMe:n=5, *P<0.001 compared to sham control (SC), #P<0.001 compared to disease control (DC) (Isoproterenol), using one-way ANOVA followed by post hoc Tukey’s test
Histopathology [Figure 6]
Figure 6.
Images (a-d) showing histopathological changes with grading in the 3heart tissue (400X H&E) (a) Sham control-No abnormality detected (0), (b) Disease Control-Mononuclear cell infiltration Multifocal myocytic necrosis, loss of sarcoplasm (+++), (c) ISP + SAM 100mg- Mild multifocal myocytic necrosis, scarring mild to moderate severity (++), (d) ISP +SAM 200mg- Necrotic areas showing scaring mild severity (+)
No abnormality was detected in (0) in SC group [Figure 6a]. The DC control group showed multifocal myocytic necrosis, loss of sarcoplasm, and marked mononuclear cell infiltration in the heart tissue. (+++) [Figure 6b]. In SAMe 100 mg group there was mild multifocal myocytic necrosis, scarring with mild to moderate severity (++) [Figure 6c]. Whereas in SAMe 200mg ISP +SAM there were necrotic areas showing scaring with mild severity (+) [Figure 6d].
Discussion
Anti-inflammatory and antioxidant properties of SAMe were evaluated in the current study using the ISO-induced CHF model. The results of our study indicated the cardioprotective role of SAMe due to these properties. S adenosylmethionine, a neutraceutical, is marketed for depression, osteoporosis, and liver disease. SAMe’s benefits in these diseases are attributed to its antioxidant and anti-inflammatory properties. Several previous studies have shown the association between oxidative stress, inflammation, and the severity of heart failure.[5] SAMe has been shown to have an antioxidant effect in the 6 OHDA-induced Parkinson’s model and an anti-inflammatory effect in NO-induced migraine in our setup.[12,13] Therefore, it was decided to address these CHF pathological targets with SAMe as a study drug. CHF also shows tissue damage, i.e., cardiac remodeling, which the antioxidant and anti-inflammatory properties of SAMe can reverse.
The selection of a validated model is important while conducting basic research in the cardiovascular area. Coronary artery ligation or embolization is used commonly by researchers for establishing the animal model of CHF. However, this model is mainly suited for large animals such as pigs and dogs because of the stringent requirements for experimental environment, equipment, and operator skills. In addition, animals are at high risk of death after surgery. CHF can be induced in rats with drugs such as adriamycin and catecholamine. Previous studies suggested that a supramaximal dose of ISO with subcutaneous injection induces excessive free radical generation, eventually leading to an inflammatory process characterized by necrosis, hyperplasia, myocardial fibrosis, and cardiac remodeling.[21] These features are almost similar to the features seen in human CHF. ISO method is preferred by many investigators due to its convenience, lower cost, and the elimination of an additional device compared to coronary artery ligation or embolization. Researchers have used this model to demonstrate the cardioprotective effects of other drugs with antioxidant or anti-inflammatory properties. Bourdier and Robelet demonstrated the cardioprotective effect of metoprolol in ISO-induced CHF due to its antioxidant properties.[22] Similarly, Thangaiyan et al. used this model to demonstrate both the anti-inflammatory and antioxidant properties of galagin to prove cardioprotective effects.[23]
In the present study, ISO 10 mg/kg for 14 days induced myocardial hypertrophy as indicated by an increased HW/BW ratio. The SAMe-treated animals in which CHF was induced showed reduced hypertrophy. Fibroblast activation and collagen secretion cause an increased extracellular matrix, leading to myocardial remodeling and affecting compliance.[24] Therefore, inhibiting fibrosis forms an important strategy to alleviate myocardial remodeling. A study by Yuanchen et al. conducted in 2022 to evaluate the cardioprotective effect of SAMe in the coronary artery ligation model showed a decrease in fibrosis and an increase in angiogenesis in the heart. In this study, SAMe treated rats have shown a decrease in extracellular collagen fibers and sma in myocardial tissues, indicating a decrease in myocardial fibrosis. The authors of this study concluded that the inhibition in myocardial fibrosis by SAMe treatment may be due to the expression of Jagged1 and Notch1 in the myocardium of rat myocardium, which promotes angiogenesis.[11]
PET scan imaging with 18F-FDG radiotracers is a useful modality to detect myocardial injury.[25] Handa et al. have shown that quantitative measurement of 18F-FDG uptake by PET scanning in the hypertrophied rat heart is reliable.[26] A previous study by Houson et al., conducted in 2017, noted the increased uptake of radiotracers in ISO-induced myocardial tissue compared to normal rats.[14] We performed 18F-FDG distribution by gamma scan throughout the whole heart. In a study by Houson et al., significantly higher distribution in DC rats was seen compared to SC rats, similar to our study results. ISO-induced cardiac damage results in significantly higher 18F-FDG uptake. This high uptake of 18F-FDG can be attributed to inflammatory cells such as neutrophils in the acute phase and in macrophages in the chronic phase of heart failure. The metabolism of cardiomyocytes is mainly based on oxidation of fatty acids. Inflammation in cardiac tissue leads to increased anaerobic glycolysis with much higher glucose levels and high 18F-FDG uptake.[27] These results contrast one reported by Houson et al.’s study on ISO-induced cardiomyopathy in rats conducted in 2020. In this study, the authors found a decrease in myocardial 18F-FDG uptake after 2 days of ISO treatment. However, the dose and duration of ISO differ in our study compared to Houson et al.[15] Handa et al. have shown that 18F-FDG uptake in rats is linearly correlated using PET and gamma scans. 18F-FDG uptake was reduced by SAMe in a dose-dependent manner compared to DC rats.[26] This suggests that SAMe has the potential to reverse myocardial injury and improve fibrosis, the healing process in the myocardium. The anti-inflammatory properties of SAMe may play an essential role in this aspect. The images obtained by the 18F-FDG-PET scan were correlated with the 18F-FDG uptake results.
Inflammation and oxidative damage correlate with each other as well as with the extent of myocardial damage. We selected TNF-α as an inflammatory marker and GSH as an antioxidant marker for our study. Systemic inflammation is considered as important contributing factor for the development and progression of heart failure. Repeated cardiac tissue injury with subsequent inflammatory cascade activation results in chronic cardiac inflammation. Therefore, anti-inflammatory treatment has been suggested to protect the heart.[28] TNF-α is the main pro-inflammatory cytokine contributing to cardiovascular disease and was selected as an inflammatory biomarker. In CHF, protective antioxidant enzymes such as superoxide dismutase and GSH are reduced along with increased production of reactive oxygen species (ROS). This overproduction of ROS contributes to myocardial remodeling (hypertrophy, fibrosis, apoptosis, and contractile dysfunction) and heart failure by in the myocardium. Modulation of endogenous anti-inflammatory and antioxidant markers provides new therapeutic targets. SAMe effectively modulated increased TNF-α and decreased GSH in diseased rats compared to disease-controlled rats. One of Chawla et al. recent studies on lipopolysaccharide-induced liver injury showed similar effects of SAMe on TNF-α and GSH serum levels.[29] In this study, these biomarker levels were measured in serum; in our study, these biomarkers were measured directly in the heart tissue. SAMe reduced TNF-α and increased GSH levels in our study compared to the DC group. SAMe acts as a precursor to GSH in the body. Previous studies have shown that exogenous SAMe intake can increase GSH levels. This contributes to the antioxidant, and ultimately, anti-inflammatory effects of SAMe.
The histopathology results with H and E staining are consistent with all parameters mentioned above, especially with 18F-FDG uptake. Sham-operated rats had normal myocardial nuclei and fewer inflammatory cells. The DC group observed greater inflammatory cell infiltration and myocardial cell damage. SAMe prevented heart cell damage and inflammatory cell infiltration. These results are similar to those of Yuanchen et al., with H and E staining showing that myocardial cell assembly was disrupted and myocardial cell number decreased in the MI group. In contrast, there was a significant improvement in the myocardial tissue of the SAMe group compared to the MI group.[11]
Conclusion
SAMe in ISO-induced CHF resulted in a decrease in HW/BW ratio and a decrease in 18F-FDG uptake in diseased heart tissue. It reduced TNF-α levels, increased GSH levels in heart tissue, and reduced myocardial damage in this model of CHF. The study results conclude that SAMe reduces myocardial damage in ISO-induced cardiomyopathy due to its ability to reduce and increase protective antioxidants and increase pro-inflammatory cytokine levels. This indicates that SAMe has the potential to be used as a cardioprotective agent in patients with heart disease to prevent nonischemic heart failure.
Further animal research should be performed with other heart-specific biomarkers such as B-type natriuretic peptide, N-terminal pro-BNP, and atria natriuretic peptide, which are clinically used biomarkers. SAMe has a DNA methylation property and is linked to epigenetic modulation of specific genes involved in inflammation and oxidative stress, which play essential roles in cardiovascular disease pathogenesis. Therefore, a specific biomarker, 5-methylcytosine, can be used as one of the biomarkers in further animal and clinical research of SAMe. A proof-of-concept clinical trial of SAMe as an add-on drug can be performed on a small number of patients as this drug is already marketed as a neutraceutical and has fewer side effects.
Author’s contribution
Conceptualization and methodology: SJ and RT; Experimentation: KK, PC, BV, and PV Data analysis: KK, SJ, RT, Supervision: SJ and RT; Original draft preparation: SJ, KK Editing and final approval: RT, PC, BV, PV.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
The authors would like to thank Dr. Sanket Gaikwad, Second-year resident, MD Pharmacology, Seth GS Medical College and KEM Hospital, Parel, Mumbai - 400 012, India for proofreading the article and rechecking the references.
Funding Statement
Nil
References
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