Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed.

Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.

A systematic review and meta-analysis of clinical trials investigating the effects of flaxseed supplementation on plasma C-reactive protein concentrations.

INTRODUCTION: Many experimental and clinical trials have suggested that flaxseed might be a potent antihypertensive, but the evidence concerning the effects of flaxseed supplements on plasma C-reactive protein (CRP) concentrations has not been fully conclusive. We assessed the impact of the effects of flaxseed supplementation on plasma CRP concentrations through a systematic review of literature and meta-analysis of available randomised controlled trials (RCTs). MATERIAL AND METHODS: The literature search included EMBASE, ProQuest, CINAHL, and PUBMED databases up to 1st February 2016 to identify RCTs investigating the effect of flaxseed supplements on plasma CRP concentrations. Meta-analysis was performed using a random-effects model, and effect size was expressed as weighed mean difference (WMD) and 95% confidence interval (CI). RESULTS: Meta-analysis of 17 selected RCTs with 1256 individuals did not suggest a significant change in plasma CRP concentrations following supplementation with flaxseed-containing products (WMD: -0.25 mg/l, 95% CI: -0.53, 0.02, p = 0.074). The effect size was robust in the leave-one-out sensitivity analysis. Subgroup analysis did not suggest any significant difference in terms of changing plasma CRP concentrations among different types of flaxseed supplements used in the included studies, i.e. flaxseed oil (WMD: -0.67 mg/l, 95% CI: -2.00, 0.65, p = 0.320), lignan extract (WMD: -0.32 mg/l, 95% CI: -0.71, 0.06, p = 0.103) and ground powder (WMD: -0.18 mg/l, 95% CI: -0.42, 0.06, p = 0.142). CONCLUSIONS: The meta-analysis of RCTs did not show a significant change in plasma CRP concentrations following supplementation with various flaxseed products. Large, well-designed studies should be still performed to validate the current results.

Acute inhibition of monoamine oxidase and ischemic preconditioning in isolated rat hearts: interference with postischemic functional recovery but no effect on infarct size reduction.

Monoamine oxidases (MAOs) have recently emerged as important mitochondrial sources of oxidative stress in the cardiovascular system. Generation of reactive oxygen species during the brief episodes of ischemic preconditioning (IPC) is responsible for the cardioprotection at reperfusion. The aim of this study was to assess the effects of two MAO inhibitors (clorgyline and pargyline) on the IPC-related protection in isolated rat hearts. Animals subjected to 30 min global ischemia and 120 min reperfusion were assigned to the following groups: (i) Control, no additional intervention; (ii) IPC, 3 cycles of 5 min ischemia and 5 min reperfusion before the index ischemia; (iii) IPC-clorgyline, IPC protocol bracketed for 5 min with clorgyline (50 µmol/L); (iv) IPC-pargyline, IPC protocol bracketed for 5 min with pargyline (0.5 mmol/L). The postischemic functional recovery was assessed by the left ventricular developed pressure (LVDP) and the indices of contractility (+dLVP/dt max) and relaxation (-dLVP/dt max). Infarct size (IS) was quantified by TTC staining. In both genders, IPC significantly improved functional recovery that was further enhanced in the presence of either clorgyline or pargyline. IS reduction was comparable among all the preconditioned groups, regardless of the presence of MAO inhibitors. In isolated rat hearts, acute inhibition of MAOs potentiates the IPC-induced postischemic functional recovery without interfering with the anti-necrotic protection.

Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues.

A substantial body of evidence indicates that pharmacological activation of mitochondrial ATP-sensitive potassium channels (mKATP) in the heart is protective in conditions associated with ischemia/reperfusion injury. Several mechanisms have been postulated to be responsible for cardioprotection, including the modulation of mitochondrial respiratory function. The aim of the present study was to characterize the dose-dependent effects of novel synthetic benzopyran analogues, derived from a BMS-191095, a selective mKATP opener, on mitochondrial respiration and reactive oxygen species (ROS) production in isolated rat heart mitochondria. Mitochondrial respiratory function was assessed by high-resolution respirometry, and H2O2 production was measured by the Amplex Red fluorescence assay. Four compounds, namely KL-1487, KL-1492, KL-1495, and KL-1507, applied in increasing concentrations (50, 75, 100, and 150 µmol/L, respectively) were investigated. When added in the last two concentrations, all compounds significantly increased State 2 and 4 respiratory rates, an effect that was not abolished by 5-hydroxydecanoate (5-HD, 100 µmol/L), the classic mKATP inhibitor. The highest concentration also elicited an important decrease of the oxidative phosphorylation in a K(+) independent manner. Both concentrations of 100 and 150 µmol/L for KL-1487, KL-1492, and KL-1495, and the concentration of 150 µmol/L for KL-1507, respectively, mitigated the mitochondrial H2O2 release. In isolated rat heart mitochondria, the novel benzopyran analogues act as protonophoric uncouplers of oxidative phosphorylation and decrease the generation of reactive oxygen species in a dose-dependent manner.

Monoamine Oxidases as Potential Contributors to Oxidative Stress in Diabetes: Time for a Study in Patients Undergoing Heart Surgery.

Oxidative stress is a pathomechanism causally linked to the progression of chronic cardiovascular diseases and diabetes. Mitochondria have emerged as the most relevant source of reactive oxygen species, the major culprit being classically considered the respiratory chain at the inner mitochondrial membrane. In the past decade, several experimental studies unequivocally demonstrated the contribution of monoamine oxidases (MAOs) at the outer mitochondrial membrane to the maladaptative ventricular hypertrophy and endothelial dysfunction. This paper addresses the contribution of mitochondrial dysfunction to the pathogenesis of heart failure and diabetes together with the mounting evidence for an emerging role of MAO inhibition as putative cardioprotective strategy in both conditions.

Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes.

Diabetes mellitus (DM) is widely recognized as the most severe metabolic disease associated with increased cardiovascular morbidity and mortality. The generation of reactive oxygen species (ROS) is a major event causally linked to the development of cardiovascular complications throughout the evolution of DM. Recently, monoamine oxidases (MAOs) at the outer mitochondrial membrane, with 2 isoforms, MAO-A and MAO-B, have emerged as novel sources of constant hydrogen peroxide (H2O2) production in the cardiovascular system via the oxidative deamination of biogenic amines and neurotransmitters. Whether MAOs are mediators of endothelial dysfunction in DM is unknown, and so we studied this in a streptozotocin-induced rat model of diabetes. MAO expression (mRNA and protein) was increased in both arterial samples and hearts isolated from the diabetic animals. Also, H2O2 production (ferrous oxidation - xylenol orange assay) in aortic samples was significantly increased, together with an impairment of endothelium-dependent relaxation (organ-bath studies). MAO inhibitors (clorgyline and selegiline) attenuated ROS production by 50% and partially normalized the endothelium-dependent relaxation in diseased vessels. In conclusion, MAOs, in particular the MAO-B isoform, are induced in aortas and hearts in the streptozotocin-induced diabetic rat model and contribute, via the generation of H2O2, to the endothelial dysfunction associated with experimental diabetes.

Monoamine oxidase--a inhibition reverses endothelial dysfunction in hypertensive rat aortic rings.

AIM: Monoamine oxidases (MAOs) are mitochondrial enzymes, with 2 isoforms, A and B that convert biogenic amines to their corresponding aldehydes via a reaction that produces hydrogen peroxide. Since MAO-A is the predominant form at vascular level we hypothesized that MAO-A-dependent H2O2 production may contribute to the development of endothelial dysfunction and, MAOs inhibition could improve the vascular function, respectively. MATERIAL AND METHODS: To this aim aortic rings were isolated from female adult spontaneously hypertensive rats (SHR) and their corresponding (Wistar-Kyoto) controls. The effect of MAO-A inhibitor, clorgyline (10 micromol/l) on endothelium-dependent relaxation (EDR) in response to acetylcholine and endothelium-independent relaxation in response to sodium nitroprusside, was studied in isolated phenylephrine-preconstricted aortic segments in the presence of indometacine (10 micromol/l). RESULTS: In hypertensive group EDR was significantly decreased - maximal relaxation (% of KCI, mean +/- SD) being 37 +/- 3.5 in SHR vs. 3.7 +/- 1.8 in controls. If experiments were done in the presence of clorgyline, EDR in control segments was unaffected. However, the compound restored normal EDR in aortic segments from hypertensive rats (maximal relaxation % of KCI, 13.7 +/- 2.3). CONCLUSIONS: Inhibition of the MAO-A isoform might be useful in restoring endothelium-dependent relaxation in this experimental model of hypertension in rat.

Serum lipoprotein (a) levels in patients with arterial hypertension.

UNLABELLED: Lp(a) is capable of deleteriously altering the balance between the procoagulant and anticoagulant, proinflammatory and anti-inflammatory, and vasorelaxing and vasoconstricting properties of the endothelium. MATERIAL AND METHOD: The purpose of this study was to investigate the serum concentration of Lp(a) and the main parameters of lipid profile in three groups of subjects: a control group that included 16 healthy subjects, 20 patients with arterial hypertension and dyslipidemia and 20 patients with arterial hypertension without dyslipidemia. Using B-mode ultrasonography, we evaluated carotid intima-media thickness (IMT) and flow mediated vasodilation (FMD) on brachial artery. RESULTS: We found significant higher Lp(a) concentrations in hypertensive patients with dislipidemia (70 +/- 55.95 mg/dL, p < 0.001) and in hypertensive patients without dislipidemia (69 +/- 52.33 mg/dL, p < 0.001), comparative with the control group (19 +/- 14.64 mg/dL). In hypertensive patients with dislipidemia we found a strong negative correlation between Lp(a) and carotid IMT (R2 = -0.75, p < 0.001) and a moderate negative correlation between Lp(a) and FMD (R2 = -0.38, p < 0.001). Lp(a) level wasn't correlated with the main parameters of lipid profile. CONCLUSIONS: These results indicated that serum Lp(a) values could play an important role in essential hypertension pathogenesis and could be considered as an individual risk factor in hypertensive patients.

The protective effect of superoxide dismutase on isolated human mammary arteries preincubated with triglyceride-rich remnant lipoproteins.

UNLABELLED: The main changes of the plasma lipid profile in patients with endothelial dysfunction are the increased triglyceride content of the lipoprotein remnant particles, the presence of the small and dense LDL particles and the decreasing of the HDL-cholesterol level. MATERIAL AND METHOD: Considering these observations, we performed "in vitro" experiments using human mammary artery rings, in order to examine the effect of the lipoprotein "remnants" on endothelium-dependent vasodilatation induced by cumulative doses (10(-9) M - 10(-4) M) of adenosine (ADP) and to study the effect on endothelial--independent vasodilatation induced by cumulative doses (10(-9) M-10(-4) M) of sodium-nitropruside (NSP), respectively. RESULTS: Our results showed that 1 hour pre-incubation with triglyceride--rich lipoprotein remnants diminished the endothelial-dependent vasodilator response to ADP, but it has not modified the endothelial-independent vasodilator response to NSP. Vascular response was expressed as maximal vasodilatation from the 10(-4)M phenilephrine (PE) induced pre-contraction, considered as reference. In the case of ADP, the maximal vasodilatation was ranged in 36.50% +/- 10.81% interval, comparing with the control group that presented a maximal vasodilatation of 66.15% +/- 19.41% (p < 0.005). In the case of NSP the maximal vasodilatation was ranged in 99.78% +/- 10.53% interval, comparing with the control that presented a maximal vasodilatation of 98.99% +/- 12.45% (p = 0.44). One hour co-incubation of the rings with a solution containing lipoprotein remnants (1% oxidized IDL (ox-IDL) and antioxidant factor (150 U/mL 10(-4) M Superoxid dismutase (SOD) significantly reduced the impairment of the vasodilatation response to ADP. Maximal vasodilatation of ox-IDL and SOD coincubated human mammary artery rings was 58.50% +/- 10.63% compared to the control, were the maximal vasodilatation was 66.15% +/- 19.41% (p < 0.01), but has not modified the vasodilatation response to NSP (99% +/- 0.53% vs control 98.99% +/- 12.45%, p = 0.56). CONCLUSION: The endothelial dysfunction induced by the triglyceride-rich lipoprotein "remnants", could contribute to the pathogenesis of atherosclerosis and the treatment with high doses of antioxidants could "protect" the endothelium against the pro-atherogenic action of the lipoprotein "remnants".

[The effects of chronic exposure to cigarette smoke on vasomotor endothelial function of guinea pig pulmonary arteries]. / Efectul expunerii cronice la fum de tigara asupra functiei vasomotorii a endoteliului arterelor pulmonare de cobai.

UNLABELLED: Chronic exposure to cigarette smoke on guinea-pigs induced a muscularization of pulmonary arterioles and endothelial dysfunction might be an early trigger of this vascular remodelling. Accordingly, the present study was aimed to evaluate the effect of a 12 weeks exposure to passive smoking on the pulmonary endothelial vasomotor function. MATERIAL AND METHOD: Vasodilator response of pulmonary arteries rings isolated in organ bath, precontracted with phenylephrine, was compared in the presence of cumulative doses (10(-9) to 10(-4) M) of endothelial-dependent (acetylcholine, ACh and adenosine-diphosphate, ADP) and independent vasodilators (sodium nitroprusside, SNP), respectively. RESULTS: Our results suggest that chronic exposure of guinea-pigs to cigarette smoke induces the impairment only of NO-mediated endothelial response (vasodilation was 9.83 +/- 4.36 % for ACh 10(-5)M vs. 39.72 +/- 16.61 % in control, p = 0.005, respectively 36.64 +/- 7.21 % for ADP 10(-5)M vs. 55.53 +/- 13.51 %, p = 0.02). CONCLUSION: The in vitro study of pulmonary arteries vasomotor function in guinea pigs chronically exposed to cigarette smoke may represent a reliable and relevant experimental model for the assessment of pulmonary endothelial dysfunction in early stages of COPD.

[Some aspects of pulmonary vascular remodelling in smokers and patients with mild COPD]. / Aspecte de remodelare vasculara pulmonara prezente la fumatori si pacientii cu BPOC usor.

An important feature of the pathophysiology of COPD patients is represented by the remodelling of pulmonary vasculature. Within this process, a pathogenic element might be the endothelial dysfunction induced by the combined effect of several factors such as: cigarette smoke, inflammatory mediators, hypoxia, mechanical stress, whose contribution differs according to the stage of the disease. The aims of our study were to characterize the structural pulmonary vascular abnormalities present in smokers and patients with mild COPD and to assess their pathophysiological importance. Serial tissue sections from fragments of pulmonary exeresis have been subjected to both morphometric analysis and histochemical examination of muscular pulmonary arteries. Our results have shown a process of arteriolar muscularization and intimal thickening of small muscular arteries in both smokers (intimal index 23.11% +/- 3.04%) and patients with mild COPD (25.62% +/- 3.06%) as compared to controls (17.86% +/- 2.96%). Correlation analysis has demonstrated that intimal thickening is significantly associated with cigarette consumption expressed as packs-years (r = 0.65, p = 0.04) whereas univariate regression has shown a moderate causal relation between the intimal collagen deposits and the degree of vascular thickening (r2=0,53 and p=0,002). In conclusion, cigarette smoking may play a central role within the pathogenesis of vascular abnormalities in patients with mild COPD.

[Prognostic value of brachial artery flow--mediated dilation and carotid artery intima-media thickness in hypertensive patients]. / Valoarea predictiva a vasodilatatiei dependente de endoteliu si a grosimii intima-media carotidiene la pacienti hipertensivi.

UNLABELLED: Endothelial vasodilator dysfunction assessed by brachial artery flow-mediated dilatation (FMD) and carotid intima-media thickening (IMT) are two indicators of subclinical atherosclerotic disease. The aim of the study was to observe if there is a relationship between FMD and IMT in a group of hypertensive patients. MATERIAL AND METHOD: We measured FMD and IMT by ultrasound in 75 subjects aged between 42 and 62 years. We examined their correlation and interaction with traditionally cardiovascular risk factors. Endothelial function was assessed by means of flow mediated dilation (FMD) on brachial artery, using B-mode ultrasonography. RESULTS: The mean value of FMD was 8.00 +/- 2.02%. We observed a moderate but significant correlation between FMD and total cholesterol (r = -0.511, p < 0.01) and between FMD and triglycerides (r = -0.325, p < 0.01). All the patients in the study were also examined by high resolution B-mode ultrasound to measure the IMT of the common carotid artery. The mean value of IMT values was 1.41 +/- 0.3 mm. The correlation between FMD and IMT was inverse, moderate and significant. In conclusion, in hypertensive patients, B-mode ultrasound intima-media thickness and FMD measurement are important tools for evaluation of arterial wall remodeling and can be used as valid markers of atherosclerosis in cardiovascular risk prediction.

Environmental factors and cardiovascular risk in young individuals.

UNLABELLED: Normal endothelial function alters physiologically with aging. Intervention of environmental factors precipitates and accelerates endothelial dysfunction progression, correlated with cardiovascular risk. AIM: To study the impact of environmental factors (smoking, nutritional habits, stress, physical activity) on the imbalance of the endothelial commuting threshold. METHODS: The questionnaire method was applied in order to identify and quantify the presence of environmental factors; an anthropometrical physical exam was performed; metabolic profile (insulin resistance HOMA-IR, lipid parameters) was assessed. Arterial elasticity was assessed with Complior (Artech Medical). RESULTS: The studied lot (n=80, 21.16 +/- 2.43 years) comprised young medicine students and showed a high incidence of: smoking (31.25%), unhealthy nutritional habits (60%), stress (60%), sedentary lifestyle (25%). The odds for endothelial function alteration were significant only in subjects who associated stress and smoking (OR=8.18, p=0.0006); in the same group, there was noticed the tendency for metabolic profile alteration, meaning insulin resistance (OR=1.19, p=ns). The association stress-smoking did not significantly influence the unhealthy nutritional habits (p=ns, OR=2.39), lipoprotein anomalies (TC > or = 190 mg/dL: p=ns, OR=0.98; LDL > or = 130 mg/dL: p=ns, OR=3.53), or the sedentary lifestyle (p=ns, OR=0.80). CONCLUSIONS: The main environmental factors which determine endothelial function imbalance in young ages are smoking and occupational stress. It is a positive stress which does not lead to significant metabolic anomalies or lifestyle changes. Though, this kind of stress leads to an unhealthy behavior: smoking. The association stress-smoking is essential in endothelial function alteration in young subjects. Primary cardiovascular prevention must focus drastically on unhealthy behaviors correction to reduce cardiovascular risk in young individuals.

[Correlations between carotid intima-media thickness and serum uric acid levels in hypertensive patients]. / Corelatiile dintre grosimea intima-media la nivelul arterei carotide interne si nivelele acidului uric seric la pacienti hipertensivi.

UNLABELLED: Intima-media thickness (IMT) of the carotid arteries assessed noninvasively by ultrasonography is now validated as a sensitive marker for atherosclerosis and it is directly associated with increased risk of cardiovascular disease. Hyperuricemia (HU) is a well-recognized risk factor for cardiovascular diseases. AIM: To evaluate the correlations between IMT and uric acid levels in patients with hypertension (HT). MATERIAL AND METHOD: Our study consisted of: a group of 30 patients with HT without HU (men 55%, mean age +/- S.D.: 50 +/- 11 years), a group of 25 patients with HT and HU (men 52%, mean age +/- S.D: 52 +/- 10 years), and a control group of 25 healthy subjects (men 55%, mean age +/- S.D: 50 +/- 11 years). All the patients in the study groups were examined by high resolution B-mode ultrasound to measure the IMT of the common carotid artery. RESULTS: IMT values were significantly higher in the patient groups (HT without HU and HT with HU) compared to the control group (0.98 +/- 0.28, 1.41 +/- 0.31 versus 0.56 +/- 0.15 mm, respectively, p < 0.001). In the patients groups, patients with HU had significantly higher carotid IMT compared to the patients without HU. In this study we have shown that higher SUA levels are associated with atherogenesis independent from hypertension. CONCLUSION: Early screening for hyperuricemia and lowering serum uric acid levels might be beneficial in slowing progression of IMT in hypertensive patients.

[Cigarette smoke extract induces endothelium dysfunction in isolated rabbit pulmonary arteries via an oxidative mechanism]. / Extractul de fum de tigara induce disfunctie endoteliala în arterele pulmonare izolate de iepure printr-un mecanism oxidativ.

In early stages of COPD, lacking hypoxemia, pulmonary arteries yet show endothelial abnormalities. This vascular impairment could be assigned to noxious effects of some cigarette smoke components. The aim of the present study was to investigate the effect of cigarette smoke extract (CSE) on endothelial vasomotor function in isolated rabbit pulmonary arteries in the presence or absence of a natural antioxidant with superoxide dismutase activity (SODn). After incubation of vascular rings with CSE (5% in organ bath) vascular responses to acetylcholine (endothelial-dependent vasodilator agent) and sodium nitroprusside (endothelial-independent vasodilator agent) were evaluated. Our results showed the impairment of endothelial dependent vasodilation (maximal relaxation expressed as % was 28.32 +/- 10.15 vs. 46.36 +/- 8.04 in the group coincubated with SODn, p < 0.01) while endothelial independent relaxation was preserved (maximal response expressed as % was 95.04 +/- 7.40 vs. 97.54 +/- 4.58 in the group coincubated with natural antioxidant, p = NS). In conclusion, the hydrosoluble components of CSE induced endothelial vasomotor function impairment, most probable, via an oxidative mechanism.