Dr Samir Mashelkar, Consultant-Life Science, Pharma,Biotech, discusses the damage caused by free radicals and how several heart conditions can be treated through antioxidant therapy
Antioxidants are those substances which inhibits oxidation or in biological terms removes harmful oxidising agents mostly free radicals , from the body of an organism. Free radicals are unstable substances which are uncharged,containing unpaired valency electrons and are highly reactive. They cause cell damage which are linked to a variety of chronic diseases, cancer and heart diseases .It is very important that a balance is maintained between antioxidants and free radicals for proper health.
Generation of free radicals
The formation of free radicals also known as reactive oxygen species starts with rapid acceptance of oxygen , setting up of NADPH oxidase , and the development of the superoxide anion radical. The superoxide anion radical is further converted to hydrogen peroxide. The free radicals are also formed by combination of myeloperoxidase, halide and hydrogen peroxide system. Myeloperoxidase in presence of chlorine converts hydrogen peroxide to hypochlorous ion which is a powerful oxidant. The most probable reactive oxygen species are singlet oxygen , superoxide anion radical , hydroxyl radical, alkoxy radical, peroxy radical, hydrogen peroxide and lipid peroxide. Also nitric acid synthetase produces peroxynitrite by reaction of nitric oxide with superoxide anion radical. Peroxynitrite is a very powerful oxidant and free radical.
How does free radicals cause damage to the cells?
Free radicals contains unpaired electrons and are continuously produced as bi-products during cellular reactions in the body.
Free radicals cause harm to cellular macromolecules like protein , DNA and cell menbranes by robbing their electrons by oxidation process thus causing oxidative damage. Free radicals reacts, mainly with the polyunsaturated fatty acids of cell membranes. The damage of polyunsaturated fatty acids is also called lipid peroxidation . It is very damaging as it is a continuous chain reaction.
How does antioxidants inhibit free radicals?
Anioxidants are substances which either lessen the formation of free radicals or neutralised them by reacting with them. Antioxidants usually donate an electron to the free radical. Once free radicals gets electrons , it forms an electron pair and gets stabilised and becomes harmless to the cells. They are also therefore called scavengers of free radicals.
There are mainly three type of antioxidants , namely, phytochemicals, vitamins, and enzymes.
A] Phytochemicals antioxidants
These are compounds that occur in nature in the form of food of plants like in fruits, vegetables, whole grains, beans, nuts and seeds. In studies carried out in laboratories many phytochemicals were found to act as antioxidants which neutralised free radicals and protecting cells from getting damage. Some minerals like selenium directly blocks the free radicals in the cells of the organism. Many phytochemicals with high antioxidant activity are not absorbed from the gut directly. Some helpful bacteria in the colon breaks down these phytochemcals and are later absorbed. Many phytochemicals help to maintain balance between themselves as antioxidants and free radicals in our body. Examples of phytochemicals are minerals such as copper, zinc, selenium along with substances such as theaflavin , gallate , allicin , piperine, curcumin, flavonoids. Theaflavin acts against hydrogen peroxide whereas gallate acts against hydroxyl groups and thus both acts as antioxidants. Allicin acts against peroxy radical and thus is an important antioxidant . Piperine and curcumin acts against hydroxyl radicals and thus are good antioxidants. Flavonoids reacts with hydrogen peroxides, hydroxyl groups and superoxide anion and thus are effective antioxidants
Vitamins are micronutrients which are required by the body in minute quantities for its proper functioning and are obtained from diet. There are two types of minerals namely, water soluble vitamins and lipid soluble vitamins.
There are total thirteen vitamins required by body for metabolism. They are namely vitamin A ( retinols), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7(biotin), vitamin B9 (folic acid or folate), vitamin B12 (cobalamins), vitamin C (ascorbic acid), vitamin D (calciferols), vitamin E (tocopherols and tocotrienols) and vitamin K (quinones). Out of these vitamin A ( retinols), vitamin C (ascorbic acid), vitamin E (tocopherols and tocotrienols) act as antioxidants.
Vitamin E captures peroxyl radicals and thus prevent damage to cells. Studies have also shown that existence of an vitamins E regeneration mechanism which is important for its antioxidant function. Vitamin E is regenerated by vitamin C. Also vitamin C donates an electron to the lipid radical in order to end the lipid peroxidation chain reaction. Vitamin A quenches singlet oxygen thereby acting as antioxidant.
C] Enzymes antioxidants
There are mainly three enzymes antioxidants namely, superoxide dismutase,catalase and glutathione peroxidase. Superoxide dismutase are found in cytosol and mitochondria of the cell. They convert superoxide ion into hydrogen peroxide. Catalase is found in peroxisomes. This hydrogen peroxide is further converted to water by catalase. Glutathione peroxidase is found in cytosol. It converts lipid hydroperoxides to their corresponding alcohols and also reduce free peroxide to water. Thus all three enzymes superoxide dismutase ,catalase and glutathione peroxidase act as antioxidants and help the body to withstand oxidative stress caused due to free radicals.
Also there is presence of physiological antioxidants like uric acid and glutathione. Uric acid mainly from plasma is a strong remover of carban oriented radicals and peoxy radicals in presence of water contaning fluids. It destroys peroxynitrite with help of vitamins C along with thiols. Glutathione is present in cytosol and is in combination with other enzymes . Glutathione by its reactions helps to remove peroxides and thus act as effective antioxidants.
The heart is a muscular organ which is located on left hand side and behind the breast bone. The heart pumps blood through its arteries and veins. The whole network comprises of what is known as the cardiovascular system.
The heart comprises of four chambers. The first chamber is the right atrium which gets deoxygenated blood from the veins and sends it to the right ventricle. The second chamber is the right ventricle which gets deoxygenated blood from right atrium and sends it to the lungs which is full of oxygen. The third chamber is the left atrium which gets oxygenated blood from the lungs and sends it to left ventricle. The fourth chamber is the left ventricle which sends oxygenated blood to the whole body. The vigorous pumping of blood by very strong contractions creates blood pressure.
Arteries of heart
- Aorta– It is the largest artery of the body. It begins from left ventricle of the heart and runs down all the way till abdomen. The aorta supplies oxygenated blood throughout the body.
Right coronary artery-It starts above the right cusp of the aortic valve and goes till right coronary sulcus. It supplies blood to the right ventricle. Left anterior desending artery-It is a branch of the left coronary artery that passes behind the pulmonary artery and ends up at the notch of the cardiac apex. The artery supplies blood to the anterolateral myocardium, apex, and interventricular septum.
- Left coronary artery-It starts from the aorta and gives to the left side of the heart. Circumflex branch of left coronary artery-It proceeds through the left part of the coronary sulcus and goes till posterior longitudinal sulcus.It gives blood to posterolateral left ventricle and the anterolateral papillary muscle.
- Pulmonary artery-It starts at the base of the right ventricle and ends in lungs. It carries deoxygenated blood from the right side of the heart to the lungs. Posterior interventricular artery- This artery goes from the posterior interventricular sulcus to the apex of the heart. It carries blood to the posterior third of the interventricular septum.
- Left marginal artery-It starts from the left atrioventricular sulcus and goes towards the apex of the heart and supplies blood to it. Sinoatrial nodal artery- It carries blood to the sinoatrial node which is the natural pacemaker centre of the heart.
Veins of heart
- Pulmonary veins– It begins from each lung helium and ends into left atrium. It carries blood from lungs to the heart.
- Inferior vena cava-It begins behind the abdomen and ends in right atrium. It transport deoxygenated blood from middle-lower part of body to right atrium.
- Superior vena cava-It starts from lower border of the first right costal cartilage and ends in right atrium. It transports deoxygenated blood from the upper half of the body to the right atrium.
- Greater cardiac vein-It starts at the apex of the heart and ends to the base of the ventricles. It gets blood from the left atrium and sends it to left side of the heart.
- Jugular veins– It starts from dura mater and ends in right atrium. It carries deoxygenated blood from the head back to the heart.
- Middle cardiac vein-It starts at the apex of the heart and ends in coronary sinus. It supplies blood from the heart to the extremeties of coronary sinus.
- Left marginal vein-It starts from left atrium and ventricle and ends in left margins of the heart. It supplies blood from heart to the extremeties. Right marginal vein-It starts from inferior margin of the heart into the right atrium and supplies blood in similar way.
- Axillary vein-It starts from lateral part of thorax, armpit and upper limbs and ends into the heart and also transports blood in the same way.
Different conditions of the heart
- Coronary artery disease-It is caused by narrowing of arteries by a cholesterol formation within the arteries leading to heart attack.
- Stable angina pectoris-It is caused by lack of required oxygen when you strain yourself.
- Unstable angina pectoris-It is caused due to not enough blood and oxygen due to narrowing of arteries.
- Myocardial infarction-It is caused by sudden death of heart muscle due to lack of oxygen as a result of narrowing of arteries.
- Arrhythmia-It is caused by abnormal electrical impulse to the heart affecting its rhythm.
- Congestive heart failure-It is caused due to weaken heart as a result of difficulty in breathing.
- Cardiomyopathy-It is caused due to widening of heart muscles.reducing heart blood driving ability.
- Myocarditis-It is caused due to any infection to the heart muscles.
- Pericarditis– It is caused due to any infection to the pericardium which lines the heart.
- Pericardial effusion– It is caused due to abnormal accumulation of fluid in the pericardial cavity.
- Atrial fibrillation– It is caused due to abnormal heartbeat as a result of improper electrical impulse.
- Pulmonary embolism– It is caused due to blockage of one of the pulmonary arteries
In your lungs
- Heart valve disease– It is caused by defect in one of the four heart valves.
- Endocarditis– It is caused by infection to inner lining of the heart.
- Mitral valve prolapsed– It is caused by abnormal backward movement of mitral valve when blood passes through it.
- Cardiac arrest– It is caused by sudden stoppage of functioning of the heart.
Free radicals in heart conditions
The information has revealed that impairment in the myocardial cell as a result of ischemia and reperfusion may be caused by formation of harmful reaction oxygen species like superoxide radical, hydrogen peroxide, and the hydroxyl radical. The connection between free radicals in ischemia-reperfusion destruction is shown by observation of different methods.
Electron spin resonance procedure have shown high free radical formation in blood after reperfusion of affected part . Electron spin resonance procedure have also shown free radical production in blood of people subjected to coronary angioplasty. During cardiopulmonary bypass surgery also there is greater free radical levels in blood .Also there is lower activity of antioxidants plasma of blood as compared to high free radicals due to aortic declamping.
It has been suggested that there is imbalance between high free radicals and low antioxidants during ischemia in heart tissue. This has been proved by factors that have an ability to influence antioxidant enzymes in the heart along with free radical removers, antioxidants and iron binding chemicals in reperfused muscle tissue of heart.
Also the actions of free radicals in reperfusion injury plays big role during fixing of cardiac surgery and heart transplantation.
Free radicals in reperfusion injury comes from inside the cells sources, like mitochondria and xanthine oxidase , or from externals origins, like neutrophils and macrophages. Any damage to myocardial tissues causes release of iron ions that induces reactions of reactive oxygen species. Reactive oxygen species formed in mitochondria causes mutations in DNA and also harms its respiration chain process during myocardial infarction. Free radicals like hydrogen peroxide changes cell permeability and causes prostacyclin release which is vasodilator causing heart damage. Other free radicals changes lipids and proteins in membranes which results cell malfunction and heart tissue damage. Nitric oxide reaction with iron forms complex which affect mitochondrial chain and DNA nitration causing cardiac dysfunction. Nitric oxide along with peroxynitrite which it forms , results in cardiac malfunction.
Antioxidants in heart
Security against free radicals by antioxidants in cardiac cells consists of four different portions of defensive activity which are in given order: preventive; chain breaking; repairing and adaptive.
The first part mostly includes enzymes whose enzymatic activity is controlled by presence of minute amount of minerals like manganese , copper , zinc and selenium. These include enzymes superoxide dismutases, glutathione peroxidises and catalase.The first part is mainly involved with control of production and spread of initial free radical species which are formed from molecular oxygen.The second part is concerned with vitamins namely , two vitamins C and E and also has carotenoids which is involved in blocking spread of subordinate radicals caused by chain reaction due to lipid peroxidation, started and controlled by initial free radicals.The third part is by blocking enzymatically production of subordinate free radicals from chain reactions end compounds. This allows ejection of molecules from the surrounding in which reactions involving metals may give rise to greater oxidative destruction. In the end of antioxidant mechanisms adaptation takes place.
During this sequence , reactive oxygen species act as a sign for stimulating the formation and delivery of exact antioxidant to the area of required activity. Use of antioxidants in heart condition is done during production of excited radicals as well as during chain reaction. Laboratory invitro and invivo procedures along with epidemiological experience have shown contrasting association between extremity of oxidative reaction producing free radicals during heart diseases and antioxidant activity , indicating the importance of antioxidant to the heart.
Many natural and artificially produced antioxidant drugs along with additives for preventive as well as for curing purpose have been put forward. Small antioxidants molecules which are frequently used are a-tocopherol, ascorbic acid, carotenoids, coenzyme Q, uric acid, vitamin A, melatonin, lipoic acid and aminoindoles. Pharmacological antioxidants, such as flavonoids and polyphenols from plants are also in use. Artificially produced antioxidants which can be used are alpha –tocopherol analogs , phenolic antioxidants like Probucol and Nitecapone, 21-aminosteroids or lazaroids , thiol group containing compounds like thiazolidine , ebselen, dithiolethiones.
Also drugs like beta-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists , and hydrogen-receptor antagonists tramp free radicals, stop lipid peroxidation and control changes in lipoproteins and thus act as antioxidants. Use of iron-chelators in animals myocardial infarction study have shown that it successfully prevents destruction by free radicals and thus act like antioxidant. Also it has been observed that there is some reduction in major adverse cardiovascular events when individuals were given diet supplemented with nuts or extra-virgin olive oil which may have antioxidant effect.Thus leading to the fact that food containing antioxidants reduces heart diseases.
Antoxidant therapy is now considered important for different heart conditions. We inferred that use of antioxidants needs more detail study to understand and know there pathophysiologoical role during different heart diseases and also need further research to identify new antioxidants.
1] Satish Balasaheb Nimse and Dilipkumar Pal . Free radicals, natural antioxidants, and their reaction mechanisms. RSC Adv.,2015, 5, 27986-28006.
2] Jasmina Mimic-Oka , Dragan V. Simic , Tatjana P. Simic FREE RADICALS IN CARDIOVASCULAR DISEASES . Medicine and Biology . Vol.6 , No 1, 1999 pp. 11 – 22.