**4. Cardiovascular diseases**

#### **4.1 Free radical cause nitric oxide**

Decreased concentrations of nitric oxide may cause constriction of coronary arteries and contribute to provocation of myocardial ischemia in coronary artery disease patients. The nitric oxide present in lower amounts exerted the vascular inflammation that could lead to oxidation of lipoproteins and foam cell formation that leads to the development of the atherosclerotic plaque [65]. These ROS actively involved in atherogenesis through their formation from enzymes of xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and nitric oxide synthase [66]. The peroxynitrites directly increases sarco/endoplasmic reticulum calcium (Ca2+ ATPase) sarco/endoplasmic reticulum calcium (SERCA) activity by S-glutathiolation and irreversible oxidation of the relevant cysteine thiols in atherosclerosis [67]. An imbalance of reduced production of NO or increased production of superoxide results in the endothelial dysfunction [68].

The dual role is performed by the nitric oxide NO in the cells, and at low concentrations, it regulates normal protective functions, but at high concentration may contribute to the pathogenesis [69]. Oxidative stress, mitochondrial dysfunction, and stress-related cell death pathways (apoptosis and necrosis) are related to the improper functioning of cardiovascular system [70]. Most ROS that are generated as by-products during mitochondrial electron transport and reactive nitrogen species (RNS) are peroxynitrites and nitric oxide, contributing to the role in the development of cardiovascular disease [71]. The specific markers of ROS are altered to inflammation that enhanced the risk of atherosclerosis by diabetes [72]. The vasodilator activity of NO may be unique among therapeutic options for management of hypertension, renal disease, and left ventricular hypertrophy [73].

#### **4.2 Free radical cause peroxynitrites**

Nitric oxide is important physiological signaling molecule also known as the endothelial-derived-relaxing factor (EDRF), and can form free radicals like peroxynitrites capable of peroxidizing the LDL and proteins [74]. Formation of peroxynitrite is augmented in inflammatory-like conditions such as ischemia-reperfusion injury in the high dose manner [75]. Proinflammatory cytokines stimulate the concerted enhancement in superoxide and NO-generating activities in the heart and causes myocardial contractile failure [76]. The protein nitration and inactivation of creatine kinase during heart failure in cardiac muscles are performed by peroxynitrites [77].

Peroxynitrite depresses myocardial contractility by decreasing the ability of Ca2+ to trigger contraction through cGMP/cGMP-dependent protein kinase pathway [78]. The peroxynitrite exposure results in reduced sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a isoform) activity is a major determinant of reduced

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*Diseases Related to Types of Free Radicals DOI: http://dx.doi.org/10.5772/intechopen.82879*

**4.3 Free radical cause lipid peroxidation**

**5. Immunological disorders**

nitric oxide synthase [88].

**5.2 Free radical cause peroxynitrites**

**5.1 Free radical cause nitric oxide**

death [80].

contractility in heart failure [79]. Peroxynitrites that are present in higher concentrations depicts a crucial pathogenic mechanism of stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders [12]. The synergistic performance of nitric oxide, superoxides, peroxynitrites are effect on mitochondrial function and cell

Abnormalities in levels of antioxidants like GSH are associated to accumulation of lipid peroxidation in chronic heart failure [81]. Increased formation of lipid peroxides and aldehydes has been observed in atherosclerosis, ischemia-reperfusion, and heart failure [82]. Atherosclerosis, the hardening of arteries under oxidative stress is related to oxidative changes of low density lipoproteins (LDL) which is an early prediction of development of cardiovascular disease [83]. The proinflammatory effects that result from the peroxidation of lipids, which provide critical structure and function in cellular membranes, are the main sites of pollutant attack in cardiovascular diseases of atherosclerosis, arrhythmia, hypertension, and stroke [84].

Peroxynitrite converts low density lipoprotein to a form recognized by the macrophage scavenger receptor and that this process is associated with modification of the protein and lipid, and with the oxidation of alpha-tocopherol to alpha-tocopherol quinine [85]. The activated macrophages are involved in the production of large amounts of nitric oxide and indirectly diminish lymphocyte proliferation [86]. Tyrosine nitration is recognized as a prevalent and significant post-translational protein modification that serves as an indicator of nitric oxide-mediated oxidative inflammatory reactions [87]. Prolonged iNOS expression peroxynitrite may exacerbate inflammatory responses mediated by NF-kappaB due to prolonged inducible

NO regulates the structural and functional activity of many immune and inflammatory cells like macrophages, T lymphocytes, antigen-presenting cells, mast cells, neutrophils, and natural killer cells [89]. The proinflammatory nature of NO is actively involved in the process of inflammation only at higher concentrations [90]. The macrophages in active state are actively engaged in the production of not only NO production but also TNFα production [91]. Stimulatory effects of NO on integrin β1 expression and Talin phosphorylation were mediated by the cGMP

Physiological role for ONOO▬ as a down-modulator of immune responses and also as key mediator in cellular and tissue injury is associated with chronic activation of the immune system [93]. In chronic inflammatory diseases, peroxynitrite formed by phagocytic cells may cause damage to DNA which acts as epitopes for the production of autoantibodies [94]. The central role of peroxynitrite is performed in the control of infections in macrophages [95]. They are produced throughout the vascular system, regulate differentiation and contractility of vascular smooth muscle cells, control vascular endothelial cell proliferation and migration, mediate

signaling pathway, which is likely involved in wound healing [92].

*Antioxidants*

**4. Cardiovascular diseases**

**4.1 Free radical cause nitric oxide**

in the endothelial dysfunction [68].

**4.2 Free radical cause peroxynitrites**

alterations in energy metabolism and mitochondrial dysfunction in neurodegenerative disorders [61]. Deposition of abnormal aggregated proteins and disruption of metal ion homeostasis are highly associated with oxidative stress [62]. The antioxdant and free radicals of lipid peroxidation and cognition, and cognitive response to an exercise intervention program, in adults with coronary artery disease at risk of dementia [63]. The brain is more susceptible to lipid peroxidation due to its high oxygen consumption, high level of redox metal ions, reduced antioxidant defense

Decreased concentrations of nitric oxide may cause constriction of coronary arteries and contribute to provocation of myocardial ischemia in coronary artery disease patients. The nitric oxide present in lower amounts exerted the vascular inflammation that could lead to oxidation of lipoproteins and foam cell formation that leads to the development of the atherosclerotic plaque [65]. These ROS actively involved in atherogenesis through their formation from enzymes of xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and nitric oxide synthase [66]. The peroxynitrites directly increases sarco/endoplasmic reticulum calcium (Ca2+ ATPase) sarco/endoplasmic reticulum calcium (SERCA) activity by S-glutathiolation and irreversible oxidation of the relevant cysteine thiols in atherosclerosis [67]. An imbalance of reduced production of NO or increased production of superoxide results

The dual role is performed by the nitric oxide NO in the cells, and at low concentrations, it regulates normal protective functions, but at high concentration may contribute to the pathogenesis [69]. Oxidative stress, mitochondrial dysfunction, and stress-related cell death pathways (apoptosis and necrosis) are related to the improper functioning of cardiovascular system [70]. Most ROS that are generated as by-products during mitochondrial electron transport and reactive nitrogen species (RNS) are peroxynitrites and nitric oxide, contributing to the role in the development of cardiovascular disease [71]. The specific markers of ROS are altered to inflammation that enhanced the risk of atherosclerosis by diabetes [72]. The vasodilator activity of NO may be unique among therapeutic options for management of hypertension, renal disease, and left ventricular hypertrophy [73].

Nitric oxide is important physiological signaling molecule also known as the endothelial-derived-relaxing factor (EDRF), and can form free radicals like peroxynitrites capable of peroxidizing the LDL and proteins [74]. Formation of peroxynitrite is augmented in inflammatory-like conditions such as ischemia-reperfusion injury in the high dose manner [75]. Proinflammatory cytokines stimulate the concerted enhancement in superoxide and NO-generating activities in the heart and causes myocardial contractile failure [76]. The protein nitration and inactivation of creatine kinase during heart failure in cardiac muscles are performed by

Peroxynitrite depresses myocardial contractility by decreasing the ability of Ca2+ to trigger contraction through cGMP/cGMP-dependent protein kinase pathway [78]. The peroxynitrite exposure results in reduced sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a isoform) activity is a major determinant of reduced

mechanism, and high level of polyunsaturated fatty acids [64].

**374**

peroxynitrites [77].

contractility in heart failure [79]. Peroxynitrites that are present in higher concentrations depicts a crucial pathogenic mechanism of stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders [12]. The synergistic performance of nitric oxide, superoxides, peroxynitrites are effect on mitochondrial function and cell death [80].
