The protective effects of coenzyme Q10 and L-carnitine against statins toxicity via pancreatic mitochondrial viability.
Statins include a widely class of drugs and can be used to treat hyperlipidemia in patients with chronic liver diseases and are the most effective drugs for lowering LDL cholesterol. Recently, it has been shown that statins also exert side effects on the pancreas and enhance the risk of developing type 2 diabetes mellitus. The objectives of the present research were to examine the possible protective effects of Co-Q10 and LC on statin toxicity on pancreatic mitochondria in vitro and in vivo. In our study, male Wistar rats received atorvastatin and lovastatin was given orally at a dose of 20 mg/kg and 80 mg/kg, respectively. However, in addition to these drugs, Co-Q10 (10mg/kg) and LC (500 mg/kg) were injected by intraperitoneal into separate groups of rats. Serum glucose and insulin levels were measured before and after treatment. After 2 weeks of treatment and taking blood tests, the pancreas was removed and probable toxic effects of statins, as well as supplementation effect of protectors on pancreatic cells and mitochondria, were assessed. The results showed that atorvastatin and lovastatin significantly increased glucose level and decreased insulin secretion. The glucose level in Co-Q10 and LC groups was significantly lower that statins groups. The finding also showed that statin-induced groups had higher rate of cytotoxicity, higher level of ROS formation, cytochrome c expulsion, and mitochondrial membrane potential collapse in comparison with controls (p<0/05). While, these factors were significantly decreased by administration of Co-Q10 and LC compared to statin groups (p<0/05), their use as protectors caused a significantly increase in serum insulin and SDH activity compared with statins alone (p<0/05). Our study provided that the using of statins plus Co-Q10 and LC could be considered as a complementary treatment strategy for patients those under higher levels of oxidative stress and inflammation. Furthermore, this supplementation can reduce the incidence of side effects of statins in patients.
Keywords: Statins; diabetogenic effects; mitochondria; coenzyme Q10; L-carnitine,
The coronary heart disease is the major cause of mortality and morbidity in individuals diagnosed with hypercholesterolemia. It was reported that coronary mortality was fourfold higher in people with a clinical diagnosis of definite hypercholesterolemia compared to the general population (Neil et al., 2004). Type 2 diabetes (T2DM) is the most prevalent metabolic syndrome that is caused by impaired synthesis or secretion of insulin (type 1) or due to resistance to insulin action (ADA, 2014). Previous studies demonstrated that the main cause of increased morbidity and mortality in people with diabetes is due to its many acute and chronic complications, including cardiovascular disease, stroke, foot ulcers, kidney diseases, neuropathy, blindness, and lower-extremity amputation (Deshpande, Harris-Hayes, & Schootman, 2008). Across all of the complications described above, the three most important risk factors of diabetes are hyperglycemia, hypertension, and hypercholesterolemia. It has been suggested that the risk of these complications can be reduced by improvements in glycemic control, blood pressure, and cholesterol level (Deshpande et al., 2008). In recent years, the prevalence of diabetes, a major lifestyle disorder, become a global burden, and it is rising steeply in developing countries (Dagogo-Jack, 2016). A number of drugs used to reduce cardiovascular risk also predispose to the development of diabetes. These include the thiazide diuretics, beta-blockers, and statins (Ponte & Dang, 2017). Statins are first choice treatment for hypercholesterolemia patients and can be decreased low-density lipoprotein (LDL) cholesterol concentrations and induce regression of atherosclerosis (van Wissen, Smilde, Trip, Stalenhoef, & Kastelein, 2005). Statins, also known as HMG-CoA reductase inhibitors, inhibit HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) an enzyme involved in the synthesis of cholesterol, especially in the liver. The decrease in cholesterol production leads to an increase in the number of low-density lipoprotein (LDL) membrane receptors, which increases the clearance of LDL cholesterol from the circulation. Statins are used to treat hyperlipidemia in patients with chronic liver diseases and are the most effective drugs for lowering LDL cholesterol (NCGC, 2014). The efficacy of statins is demonstrated by different surveys that show statin therapy lowers morbidity and mortality about 10% of the patients. Recent studies suggested that statins are associated with an enhanced risk of developing type 2 diabetes mellitus (T2DM) (Olokoba, Obateru, & Olokoba, 2012; Whiting, Guariguata, Weil, & Shaw, 2011). Although precise mechanism(s) of diabetogenesis with statin therapy are under active investigation, there are several hypotheses including impaired insulin sensitivity and compromised β-cell function via enhanced intracellular cholesterol, decreased insulin secretion, insulin resistance and hepatotoxicity (Gluba-Brzozka, Franczyk, Toth, Rysz, & Banach, 2016; Sattar et al., 2014). The statins decreased glucose transporter (GLUT)-2 and -4 expressions in pancreas, muscle, and adipocytes, and lead to decrease insulin secretion and increase insulin resistance. These drugs Statins are metabolized to reactive metabolites and increase the formation of reactive oxygen species (ROS) in the liver that causes hepatotoxicity and interfere in lipid peroxidation and mitochondrial injury (Bouitbir et al., 2016; Ristow & Schmeisser, 2014). Other studies showed that statins promote cell death mediated by mitochondrial dysfunctions, interaction in calcium homeostasis, inhibition of beta-oxidation, inhibition of complex I of the electron transport chain and mitochondrial oxidative stress (Busanello et al., 2017). Recently studies suggest the possible protective mechanism of L-carnitine (LC) and coenzyme Q10 (Co-Q10) on statin toxicity (N Abdoli, Azarmi, & Eghbal, 2015; La Guardia, Alberici, Ravagnani, Catharino, & Vercesi, 2013). LC, an essential mitochondrial respiratory cofactor, plays an important role in the transmission of long chain fatty acids from cytosol to mitochondria. In addition, LC can also improve the antioxidant status and free radical scavenging activity. LC was also disclosed to protect lipid peroxidation by reducing the formation of hydrogen peroxide (Abdoli et al., 2015). Co-Q10 is one of the most important lipid antioxidants, which prevents the production of free radicals and changes in proteins, lipids, and DNA. Under many conditions of diseases that are related to increased production and action of reactive oxygen species (ROS), the concentration of Co-Q10 in the human body decreases and the deficiency of Co-Q10 leads to respiratory chain dysfunction. This lack of production of highly energetic compounds may reduce the efficiency of cells (Saini, 2011). A growing body of research suggests that using Co-Q10 supplements alone or in combination with other drug therapies and nutritional supplements may be used for preventing or treating some disorders including primary and secondary Co-Q10 deficiencies, mitochondrial diseases, fibromyalgia, cardiovascular disease, neurodegenerative diseases, cancer, diabetes mellitus, male infertility, periodontal disease, acquired immune deficiency syndrome (AIDS), gastric ulcers, allergy, migraine headaches, kidney failure, muscular dystrophy, and aging (Saini, 2011). The statin medications reduce the production of mevalonate which is the precursor of isoprenoids and cholesterol. This reduction in isoprenoids, which decrease prenylated proteins, reducing cholesterol which can alter cell structure and function, reductions in dolichol and Co-Q10 (Wood, Mΰller, & Eckert, 2014). One side effect of statins is decreased the production of Co-Q10, which required for the respiratory chain, that reduced ATP synthesis causes insulin resistance and reduced insulin sensitivity leads to reduction in generation of ATP (Montgomery & Turner, 2015). Statin-mediated Co-Q10 depletion decreases mitochondrial activity of muscle that can induce insulin resistance (Alam & Rahman, 2014). Also, both LC and Co-Q10 can act directly as free radical scavenger would protect against statin-induced oxidative damage in skeletal muscle mitochondria (N Abdoli et al., 2015). Therefore, the objectives of the present research were to examine the possible protective effects of LC and Co-Q10 on statin toxicity on pancreatic mitochondria in vitro and in vivo.
- Materials and Methods
All chemicals used were of analytical grade and purchased from Sigma Chemical Co. (St. Louis, MO, USA).
- Animals’ treatment
This study was conducted under the supervision of ethical committee of Shahid Beheshti University of Medical Sciences for its accordance with the Guide for the Care and Use of Laboratory Animals published by the National Academy of Sciences. Male Wistar rats weighing 200–250 g were used in this study. At the standard laboratory, the rats had been fed a commercial rodent diet and were housed at 22±2
˚C on a12 h light-dark cycle with free access to food and water.
- Experimental design
Two experimental groups (atorvastatin and lovastatin) and two experimental setups (1 and 2) were designed to limit experimental procedures in experimental animals. In setup 1, control animals received saline and treated samples with atorvastatin and lovastatin was given orally to male rat at a dose of 20 mg/kg and 80 mg/kg, respectively. Setup 2 was carried out in a similar manner as setup 1, however, in addition of these drugs Co-Q10 (10mg/kg) and LC (500 mg/kg) were injected by intraperitoneal into separate groups of rats. Serum glucose and insulin levels were measured before and after treatment with glucometer and insulin ELISA kits. After 2 weeks of treatment and taking blood tests, the pancreas was removed and the apoptogenic, diabetogenic and apoptotic effects of drugs and protectors on pancreatic cells and mitochondria were assessed.
- Isolation of mitochondria from pancreas
Mitochondria were prepared from Wistar rat’s pancreas based on the method described by Law and Rudnicka (2006) with some modification. After homogenizing of tissues, the nuclei and broken cell debris were sedimented through centrifuging at 1500×g for 10 min at 4ºC and the pellet was discarded. The supernatant was subjected to a further centrifugation at 10,000×g for 10 min and the superior layer was carefully discarded. After washing and centrifuging (10,000×g for 10 min), the mitochondrial pellets were suspended in Tris buffer containing (0.05 M Tris-HCl, 0.25 M sucrose, 20 Mm KCl, 2.0 mM MgCl2, and 1.0 mM Na2HPO4, pH of 7.4) at 4˚C, except for the mitochondria used to assess ROS production and MMP, which were suspended in respiration buffer (0.32 mM sucrose,10 mM Tris, 20 mM Mops, 50 μM EGTA, 0.5 mM MgCl2, 0.1 mM KH2PO4 and 5 mM sodium succinate ) and MMP assay buffer (220 mM sucrose, 68 mM D-mannitol, 10 mMKCl, 5 mM KH2PO4, 2 mM MgCl2, 50 μM EGTA, 5 mM sodium succinate, 10 mM HEPES, 2 μM Rotenone). Mitochondria were prepared freshly for each experiment and kept in a dried condition on ice for a maximum of 4 h to guarantee the isolation of high-quality mitochondrial preparation.
- MTT assay
The viability of pancreatic cells was detected by Methylthiazol tetrazolium assay as described by Corpier et al. (1988). Cells were seeded onto 96-well plates and following applied treatment, 10 μL/well of methyl thiazol tetrazolium (MTT) solution was added. Afterward, DMSO (200 μl/well) was added to dissolve the crystals. The plate was allowed to stand for 10 min, and the absorbance of soluble dye was measured at 590 nm with a microplate spectrophotometer (2550, Shimadzu, Japan). MTT OD value of treatment groups was normalized to the untreated control group.
- Determination of Mitochondrial ROS Level
The reactive oxygen species (ROS) is detected and measured by method as
previously described (Hippisley-Cox & Coupland, 2010). Briefly, the isolated mitochondria from the pancreas were placed in respiration buffer. Afterward, DCFH-DA (dichloro-dihydro-fluorescein diacetate, fluorescent probe used for ROS measurement) was added (final concentration, 10 M) to the mitochondria suspension and then incubated for 15 min. at 37˚C. The fluorescence intensity of DCF (dichlorofluorescein) in ROS level determination based on treatment groups in the mitochondria obtained from pancreases rats was measured using a fluorescence spectrophotometer at the EXλ= 488 nm and EMλ=527 nm (Agarwal, 2004).
- Cytochrome c oxidase activity
The levels of cytochrome c from mitochondria by atorvastatin and lovastatin were measured using the Quantikine® Rat/Mouse cytochrome c Immunoassay kit obtained from R&D Systems (Minneapolis, MN, USA).
- Determination of the mitochondrial membrane potential (MMP)
The MMP in treated groups was measured in the mitochondria obtained from the rat pancreas. The cytosolic Rh 123 fluorescence intensity which indicates the redistribution of the Rh 123 from mitochondria into the cytosol was determined at the EXλ= 490 nm and EMλ=535 nm (Agarwal, 2004)
- Statistical analyses
The results of this study are presented as mean±SD (n=3). The statistical analyses were performed using the GraphPad Prism software (version 5). Assays were performed 3 times. Statistical significance (set at <0.05) was carried out using one-way and two-way ANOVA test.
- Protective effect of Co-Q10 and LC against statins
In order to investigate the effect of statins (lovastatin, atorvastatin) on cytotoxicity of pancreatic cells and mitochondria, as well as their combination effect with Co-Q10 and LC, we used these drugs for in vitro assessment the effects and given orally to male rats to assess the in vivo effects. Atorvastatin and lovastatin significantly can develop diabetes type 2 by increasing glucose level and decreasing insulin secretion (p<0.05). Table 1 has illustrated the protective effect of co-administration of Co-Q10 and LC for development of diabetes by statins.
The most toxic statin was atorvastatin, but CoQ10 and LC effectively reduced glucose level that induced by statins. Statins significantly decreased insulin level and increased the levels of glucose, which is an indicator of an increase in incidence of diabetes.
- MTT assay
The effects of atorvastatin and lovastatin on succinate dehydrogenase (SDH) activities (determined as % of enzyme activity) were measured by the MTT assay, using mitochondria obtained from pancreas following 1 hr of incubation. Fig. 1(A) shows that administration of 20 mg/kg atorvastatin significantly decreased the viability of pancreatic cells in comparison with control group (p<0/05), and pretreatment effect of both CO-Q10 and LC on SDH activity in comparison with atorvastatin group was significant (p<0.05).
Fig. 1(B) demonstrated that 80 mg/kg lovastatin decreased succinate dehydrogenase activity (viability) compared to control group and the protective effect in both CO-Q10 and LC was very low, so the difference between lovastatin and pre-treated groups with CO-Q10 and LC was not significant (p>0.05). Our results showed that atorvastatin was much more toxic than lovastatin toward pancreatic mitochondria.
- Mitochondrial ROS Level
As shown in Fig. 2 (A and B), the presence of atorvastatin and lovastatin-induced significant (0<0.05) H2O2 formation demonstrated as fluorescence intensity emitted from highly fluorescent DCF (dichlorofluorescein) in the mitochondria obtained from the pancreas. The results also showed that the administration of CO-Q10 and LC decreased the toxic effect of statins on ROS formation (Fig. 2). The results also showed that atorvastatin was much more effect than lovastatin toward ROS formation.
- Cytochrome c oxidase activity
As shown in Fig. 3, results indicate that atorvastatin and lovastatin at a concentration of 20 mg/kg 80 mg/kg induced significant (0< 0.001) expulsion of cytochrome c (ng/mg mitochondrial protein) in the mitochondria obtained from the pancreas. Pre-treatment of rats with Co-Q10 and LC decreased statin-induced cytochrome c release in comparison with atorvastatin and lovastatin groups (0< 0.05).
- Mitochondrial Membrane Potential (MMP)
Mitochondrial membrane potential (∆Ψm), as an important factor in assessment of mitochondrial functionality, showed that atorvastatin and lovastatin caused mitochondrial dysfunction and intensity of fluoresce (Fig. 4 and 5). Co-administration of CO-Q10 and LC effectively protected cellular mitochondria against statins induced injury as revealed by an improvement in mitochondrial membrane potential (p<0/05).
According to the data obtained from current investigation, it seems that atorvastatin had more apoptotic effect on isolated rat pancreases since it caused a higher rate of cytotoxicity (Fig. 1), higher level of ROS formation (Fig. 2), Cytochrome c expulsion (Fig. 3), and mitochondrial membrane potential collapse in comparison with lovastatin (Fig. 4 and 5).
The statins are one of the most widely recommended groups of drugs in the globe and beneficial in prevention of cardiovascular disease. The adverse effects of statins such as liver toxicity (Law & Rudnicka, 2006), diabetes risk (Carter et al., 2013), rhabdomyolysis and myopathy (Corpier et al., 1988; Hippisley-Cox & Coupland, 2010) and renal injury (Agarwal, 2004) have been reported. In some studies, the risk of diabetes in patients receiving statins (e.g. rosuvastatin, lovastatin, atorvastatin and simvastatin) has been investigated (Aiman, Najmi, & Khan, 2014; Zaharan, Williams, & Bennett, 2013). Emerging evidence shows that therapy with statins raises the risk of T2DM (Sadighara et al., 2017). Although, the mechanisms of induction of diabetes with the consumption of statins are not fully understood. Previously published studies have indicated that one of the mechanisms of statin-induced diabetes is an increase in insulin resistance, which is reflected through hyperglycemia (Cederberg et al., 2015; Erqou, Lee, & Adler, 2014; Sattar et al., 2014). In our study, it was shown that atorvastatin and lovastatin could potentially induce an increase in blood glucose and decrease in insulin secretion in the pancreas. Recently studies suggest the possible protective mechanism of CO-Q10 and LC on statin toxicity (N Abdoli et al., 2015; La Guardia et al., 2013). Present study illustrated protective effect of co-administration of Co-Q10 and LC for development of diabetes by statins.
On the other hand, hyperglycemia induces free radical production such as H2O2 that it impairs the endogenous antioxidant defense system in patients with diabetes and leads to domination of the condition called oxidative stress (Tiwari, Pandey, Abidi, & Rizvi, 2013). Statins treatment can impair mitochondrial biogenesis by production of a large amount of ROS and trigger deleterious effects on mitochondrial function (Bouitbir et al., 2012). Our study showed that atorvastatin and lovastatin were able to raise the generation of ROS (especially of H2O2) in pancreas mitochondria by induced hyperglycemia. It seems the mechanism of statins for disruption in mitochondrial dysfunction in skeletal muscles and pancreas is same (Aiman et al., 2014).
Recently Co-Q10 and LC are considered as two important protectors of statins side effects on different isolated mitochondria. Our results were in accordance with other studies demonstrating that usage of antioxidants such as Co-Q10 and LC reduce stress oxidative and toxic effect of statin-induced injury (N Abdoli et al., 2015; Ben‐Meir et al., 2015). Co-Q10 and LC act as potent antioxidants by scavenging ROS for protecting cells against oxidative stress in many diseases (Costa, Fernandes, de Souza-Pinto, & Vercesi, 2013; Noh et al., 2013).
In the present study, the diabetogenic and apoptotic effects of atorvastatin and lovastatin on isolated rat’s pancreatic mitochondria in addition to protective role of Co-Q10 and LC in vitro and in vivo were assessed. The results proved that Co-Q10 and LC can reduce the toxic effect of statins and improve mitochondrial dysfunction during 2-week treatment. Previous studies reported that statin treatment (such as atorvastatin and lovastatin) reduces the levels of Co-Q10, which is part of electron transport chain (ETC) involved in the process of ATP production (Aiman et al., 2014; Mabuchi et al., 2005).
In the one hand, an increase of cytochrome c release from mitochondria also occurs upon treatment with statins, indicating activation of the intrinsic pathway (Kato et al., 2010). On the other hand, Co-Q10 pretreatment inhibited mitochondrial damage, expression of cytochrome c and cell apoptosis (Chen et al., 2013). The same inhibitory effect was reported by LC administration (Chao et al., 2011). This study, therefore, addresses the anti-apoptotic activities of Co-Q10 and LC in rats treated with atorvastatin and lovastatin.
Our data showed that statins induce significant changes in MMP and mitochondrial outer membrane damage. Narges Abdoli, Azarmi, and Eghbal (2014) showed treating hepatocytes with the statins produces a significant amount of ROS, induces lipid peroxidation, reduces MMP and promotes cytotoxicity as compared to the control group.
Treatment with statins plus Co-Q10 and LC significantly altered the above effects indicating antioxidant activity. Therefore, current results provide evidence that supplementation of statins with Co-Q10 and LC shows synergistic effect in reducing glucose level, ROS formation in pancreas, cytochrome c release, cellular mitochondrial potential, mitochondrial outer membrane damage and MMP, as well as their effect in raising serum insulin and SDH activity.
Statins interference in production of Co-Q10 prompted and its deficiency may play a role in statin-associated adverse effects. Our study provided that the using of statins plus Co-Q10 and LC could potentially induce decreased blood glucose and increased insulin level in the pancreas compared with statins alone. We suggest that Co-Q10 and LC supplementation could be considered as a complementary treatment strategy for patients those under higher levels of oxidative stress and inflammation. Furthermore, this supplementation can reduce the incidence of side effects and patients could better tolerate their statin therapy.
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Figure 1: The effect of atorvastatin (ATO) and lovastatin (LOV) alone and in supplementation with Co-Q10 and LC on SDH activity. The SDH activity was measured using MTT assay. Data represented as mean±SD of data determined from three separate experiments. The two-way ANOVA test was performed.
*, **, and ***significantly different from the corresponding control (p<0.05, p<0.01 and p<0.001, respectively).
## significant difference in comparison atorvastatin (20 mg/kg) and lovastatin (80 mg/kg) groups (p<0.01).
Figure 2: Measurement of mitochondrial ROS formation in rat pancreas. The ROS level was assayed after treatment with atorvastatin (ATO) and lovastatin (LOV) alone and in supplementation with Co-Q10 and LC. The two-way ANOVA test was performed.
* and *** significantly different from the corresponding control (p<0.05 and p<0.001, respectively).
## and ### significant difference in comparison with atorvastatin (20 mg/kg) and lovastatin (80 mg/kg) groups (p<0.01 and p<0.001, respectively).
Figure 3: Cytochrome c expulsion assay. The cytochrome c expulsion was assayed after treatment with atorvastatin (ATO) and lovastatin (LOV) alone and in supplementation with Co-Q10 and LC. The two-way ANOVA test was performed.
*, **, and *** significantly different from the corresponding control (p<0.05, p<0.01 and p<0.001, respectively).
## significant difference in comparison with atorvastatin (20 mg/kg) and lovastatin (80 mg/kg) groups (p<0.01).
Figure 4: Statins-induced collapse in cellular mitochondrial potential (∆Ψm) and the role of CO-Q10 and LC administration. Rhodamine 123 test was employed to assess the mitochondrial membrane potential.
*, **, and *** significantly different from the corresponding control (p<0.05, p<0.01 and p<0.001, respectively).
## and ### significant difference in comparison with atorvastatin (20 mg/kg) and lovastatin (80 mg/kg) groups (p<0.01).
Figure 5: Statins-induced mitochondrial outer membrane damage and protective effects of CO-Q10 and LC.
*** significantly different from the corresponding control (p<0.001).
### significant difference in comparison with atorvastatin (20 mg/kg) and lovastatin (80 mg/kg) groups (p<0.001).
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