**5. Nitroso-redox balance in the cardiovascular system**

Oxidative stress is always associated with ischemia reperfusion injury, dilated cardiomyopathy, and heart failure [80]. It is crucial to restore redox balance in the cardiovascular system when treating these diseases. Redox balance is governed by changes in the oxidative state in tissues, where addition and loss of electrons result in reduction and oxidation of molecules, respectively [80]. Oxygen can accept an electron to become reactive oxygen species (ROS). ROS are highly reactive chemical species that contain oxygen atoms, mostly free radicals with one or more unpaired electrons [81]. NO is a free radical signaling molecule. Under pathological conditions, it reacts with superoxide to generate reactive nitrogen species (RNS) that have detrimental consequences to cells. Herein, we highlight the causes of redox imbalance, their functions in the cardiovascular system, and the roles they play in the progression of CVDs.

#### **5.1 Biochemistry and physiology of ROS and RNS**

#### *5.1.1 ROS and oxidative stress*

The electron transport chain (ETC) located in the inner membrane of mitochondria is crucial for energy and ROS generation (**Figure 3**). Normally, the final electron acceptor oxygen is reduced to water. However, in pathological conditions, electrons uncouple from the chain and react with oxygen without passing *cytochrome c* oxidase to form superoxide. Other ROS sources include NADPH oxidase, xanthine oxidase (XO), eNOS, and cytochrome P450s (CYP). NADPH oxidases belong to NOX family proteins, which transfer electrons across intracellular membranes. NADPH oxidases transfer electron from NADPH to oxygen to form superoxide for immune responses [82, 83]. Three NOX enzymes have been found in the vascular wall, NOX 1, 2, and 4. NOX 1 and 2 result in the formation of superoxide and NOX 4 produces hydrogen peroxide (H2O2) [83]. NOX 4 is also present in the mitochondria and SR in cardiomyocytes [80]. XO is found in the heart and ECs. It catalyzes purine metabolism with superoxide and H2O2 produced. The activity of XO is enhanced under ischemic reperfusion injury and oscillatory shear stress [83, 84]. Another important source of ROS is the uncoupling of eNOS, which causes eNOS to produce superoxide, instead of NO. One of the reasons for eNOS uncoupling is the deficiency in the substrates (L-arginine and oxygen) and co-factor BH4 [80, 83]. Uncoupling of eNOS may explain why diabetic patients are susceptible to CVDs. High glucose increases arginase levels in ECs, which competes with eNOS for the substrate L-arginine [85]. In addition, overload of ROS in diabetes mellitus limits BH4 biosynthesis to further facilitate eNOS uncoupling [86]. Cytochrome p450s (CYP) are a group of hemoproteins similar in structure and function to eNOS under oxidative stresses. The catalytic activity of CYP requires oxygen and two electrons to form a ferrous-dioxy complex [87]. CYP is involved in the metabolism of cholesterol, vitamins, and arachidonic acid [88]. When there is excessive oxygen consumed, the enzyme uncouples, and the ferrous-dioxy complex diverts back to the ferric state to produce superoxide [89].

Superoxide is an anion-free radical that can produce other ROS including H2O2, hydroxyl radicals (. OH), and hypochlorous acid (HClO) [80, 82, 90, 91].

**13**

**Figure 3.**

*Nitric Oxide and Oxidative Stress-Mediated Cardiovascular Functionality: From Molecular…*

The spontaneous transfer of an electron to superoxide at low pH or by an enzyme reaction (superoxide dismutase, SOD) produces H2O2 [82, 91]. Low levels of H2O2 (1–10 nM) induce more antioxidant molecules that protect the cells, and high levels (>100 nM) are likely to generate more prooxidants [91]. For example, high level of H2O2 was generated in neutrophils for antimicrobial effects [92, 93]. Hydroxyl radical can be formed from the reaction between H2O2 and superoxide (Haber Weiss reaction) or the breakdown of H2O2 by metal ions, Fe2+ or Cu2+ (Fenton reaction) [94]. Hydroxyl radical is highly reactive. It alters DNA structure by attacking purine and pyrimidine bases, leading to mutations and cell damages [95]. In the pathological myocardial tissue, it is associated with decreased contractile function, increased membrane phospholipid peroxidation, and heart failure [96, 97]. HClO is mainly produced by leukocytes when H2O2 reacts with chloride anions. It facilitates the removal of foreign particles and is also implicated in the progression of atheroscle-

NO acts in a diffusion- and concentration-dependent manner. Low concentrations of NO (nanomolar range) have a protective role, while high NO levels (micromolar range) can be detrimental [98]. The majority of NO's biological effect is attributed to sGC/cGMP pathway [21]. Additionally, NO acts as a signaling mediator through S-nitrosylation. NO can inhibit cardiac hypertrophy through nitrosylation of histone deacetylase 2 (HDAC2) released from chromatin [99]. HDAC2 regulates anti-hypertrophic genes. In ischemic preconditioning (the body's defense mechanism against myocardial necrosis), the S-nitrosylation of mitochondrial proteins protects the mitochondria from oxidative stress [100]. S-nitrosylation initiates excitation contraction coupling by increasing Ca2+ uptake, and the contraction may be sustained through releasing of Ca2+ via SR membrane ryanodine receptors

*DOI: http://dx.doi.org/10.5772/intechopen.82556*

rosis and ischemic reperfusion injury [81].

*The major sources of ROS and RNS in the cardiovascular system.*

*5.1.2 NO and nitrosative stress*

*Nitric Oxide and Oxidative Stress-Mediated Cardiovascular Functionality: From Molecular… DOI: http://dx.doi.org/10.5772/intechopen.82556*

#### **Figure 3.**

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

**5. Nitroso-redox balance in the cardiovascular system**

**5.1 Biochemistry and physiology of ROS and RNS**

the ferric state to produce superoxide [89].

H2O2, hydroxyl radicals (.

biologically relevant.

the progression of CVDs.

*5.1.1 ROS and oxidative stress*

the NO reservoir to catalyze NO generation from S-nitrosoglutathione or nitrite in the body. Currently, its main challenge is to adjust the NO releasing rate to be more

Oxidative stress is always associated with ischemia reperfusion injury, dilated cardiomyopathy, and heart failure [80]. It is crucial to restore redox balance in the cardiovascular system when treating these diseases. Redox balance is governed by changes in the oxidative state in tissues, where addition and loss of electrons result in reduction and oxidation of molecules, respectively [80]. Oxygen can accept an electron to become reactive oxygen species (ROS). ROS are highly reactive chemical species that contain oxygen atoms, mostly free radicals with one or more unpaired electrons [81]. NO is a free radical signaling molecule. Under pathological conditions, it reacts with superoxide to generate reactive nitrogen species (RNS) that have detrimental consequences to cells. Herein, we highlight the causes of redox imbalance, their functions in the cardiovascular system, and the roles they play in

The electron transport chain (ETC) located in the inner membrane of mitochondria is crucial for energy and ROS generation (**Figure 3**). Normally, the final electron acceptor oxygen is reduced to water. However, in pathological conditions,

Superoxide is an anion-free radical that can produce other ROS including

OH), and hypochlorous acid (HClO) [80, 82, 90, 91].

electrons uncouple from the chain and react with oxygen without passing *cytochrome c* oxidase to form superoxide. Other ROS sources include NADPH oxidase, xanthine oxidase (XO), eNOS, and cytochrome P450s (CYP). NADPH oxidases belong to NOX family proteins, which transfer electrons across intracellular membranes. NADPH oxidases transfer electron from NADPH to oxygen to form superoxide for immune responses [82, 83]. Three NOX enzymes have been found in the vascular wall, NOX 1, 2, and 4. NOX 1 and 2 result in the formation of superoxide and NOX 4 produces hydrogen peroxide (H2O2) [83]. NOX 4 is also present in the mitochondria and SR in cardiomyocytes [80]. XO is found in the heart and ECs. It catalyzes purine metabolism with superoxide and H2O2 produced. The activity of XO is enhanced under ischemic reperfusion injury and oscillatory shear stress [83, 84]. Another important source of ROS is the uncoupling of eNOS, which causes eNOS to produce superoxide, instead of NO. One of the reasons for eNOS uncoupling is the deficiency in the substrates (L-arginine and oxygen) and co-factor BH4 [80, 83]. Uncoupling of eNOS may explain why diabetic patients are susceptible to CVDs. High glucose increases arginase levels in ECs, which competes with eNOS for the substrate L-arginine [85]. In addition, overload of ROS in diabetes mellitus limits BH4 biosynthesis to further facilitate eNOS uncoupling [86]. Cytochrome p450s (CYP) are a group of hemoproteins similar in structure and function to eNOS under oxidative stresses. The catalytic activity of CYP requires oxygen and two electrons to form a ferrous-dioxy complex [87]. CYP is involved in the metabolism of cholesterol, vitamins, and arachidonic acid [88]. When there is excessive oxygen consumed, the enzyme uncouples, and the ferrous-dioxy complex diverts back to

**12**

*The major sources of ROS and RNS in the cardiovascular system.*

The spontaneous transfer of an electron to superoxide at low pH or by an enzyme reaction (superoxide dismutase, SOD) produces H2O2 [82, 91]. Low levels of H2O2 (1–10 nM) induce more antioxidant molecules that protect the cells, and high levels (>100 nM) are likely to generate more prooxidants [91]. For example, high level of H2O2 was generated in neutrophils for antimicrobial effects [92, 93]. Hydroxyl radical can be formed from the reaction between H2O2 and superoxide (Haber Weiss reaction) or the breakdown of H2O2 by metal ions, Fe2+ or Cu2+ (Fenton reaction) [94]. Hydroxyl radical is highly reactive. It alters DNA structure by attacking purine and pyrimidine bases, leading to mutations and cell damages [95]. In the pathological myocardial tissue, it is associated with decreased contractile function, increased membrane phospholipid peroxidation, and heart failure [96, 97]. HClO is mainly produced by leukocytes when H2O2 reacts with chloride anions. It facilitates the removal of foreign particles and is also implicated in the progression of atherosclerosis and ischemic reperfusion injury [81].

#### *5.1.2 NO and nitrosative stress*

NO acts in a diffusion- and concentration-dependent manner. Low concentrations of NO (nanomolar range) have a protective role, while high NO levels (micromolar range) can be detrimental [98]. The majority of NO's biological effect is attributed to sGC/cGMP pathway [21]. Additionally, NO acts as a signaling mediator through S-nitrosylation. NO can inhibit cardiac hypertrophy through nitrosylation of histone deacetylase 2 (HDAC2) released from chromatin [99]. HDAC2 regulates anti-hypertrophic genes. In ischemic preconditioning (the body's defense mechanism against myocardial necrosis), the S-nitrosylation of mitochondrial proteins protects the mitochondria from oxidative stress [100]. S-nitrosylation initiates excitation contraction coupling by increasing Ca2+ uptake, and the contraction may be sustained through releasing of Ca2+ via SR membrane ryanodine receptors

(RyRs) [26]. Quantitatively, when three thiols per subunit of RyR channels are nitrosylated, the process is reversible. However, if six or more thiols per subunit are nitrosylated, irreversible Ca2+ ion release occurs and can be detrimental to the cardiac muscle [26]. In addition, when too much NO is generated during inflammation or sepsis, NO may cause hypovolemia due to its excessive vasodilation effect [83]. Furthermore, upregulation of iNOS in ECs reduces the availability of BH4 to eNOS, intensifying eNOS uncoupling and superoxide generation [83]. Thus, the physiological role of NO can be attenuated by ROS, because NO is quickly consumed by superoxide before it initiates any cell response [101].

When NO collides with superoxide, peroxynitrite (ONOO<sup>−</sup>) is formed, causing nitrosative stress. The chemical reaction is very fast and deleterious [98]. ONOO<sup>−</sup> is a very strong oxidant. It reacts with proteins through tyrosine and tryptophan residues to form nitrotyrosine and nitrotryptophan, respectively [80, 98]. In diabetic mice, tyrosine nitration of the voltage-gated K<sup>+</sup> channels in the vascular SMCs altered its dilation function, a possible mechanism of the progression of coronary artery disease [102]. Tyrosine nitration was also observed in cardiac myocytes desmin, myosin heavy chain, α-actin, and microtubules. These proteins play pivotal roles in maintaining cell morphology and cardiac contractility [98]. When free nitrotyrosine was incorporated into the carboxyl terminus of α-tubulin in microtubules, altered microtubule organization and redistribution of the motor cytoplasmic protein dynein were observed [103]. Protein activity can also be impaired by oxidation of thiols to disulfide bond by ONOO<sup>−</sup> [98]. In addition, ONOO<sup>−</sup> also reacts with lipids to yield nitrated lipids to promote atherosclerosis, and with nucleic acids via guanine and the sugar phosphate backbone to damage DNA [98].

On the other hand, low concentrations of ONOO<sup>−</sup> (10–200 uM) is associated with tyrosine kinase-dependent signaling. ONOO<sup>−</sup> has been shown to activate tyrosine phosphorylation and trigger glycolysis [98]. Another example involves MAPK pathway, where ONOO<sup>−</sup> activates Raf-1 kinase. The MAPK pathway is closely associated with anti-apoptosis and cardiac hypertrophy in the cultured cardiomyocyte model [104].

#### **5.2 Atherosclerosis**

#### *5.2.1 Inflammatory mechanism of atherosclerosis*

Atherosclerosis is characterized by the formation of plaques that reduce the lumen of arteries and consequently interfere with blood flow and tissue perfusion. The plaque consists of the lipid core and fibrous cap. In patients with hypercholesterolemia, ROS and RNS oxidize low-density lipoprotein (LDL) [105]. Oxidized LDL (Ox LDL) initiates a cascade of events that alters the endothelial permeability and leads to insudation of the lipoprotein in the arterial wall. Stimulated by atheroprone signals, ECs express selectins and vascular cell adhesion molecule (VCAM-1) to attract circulating blood monocytes. Monocytes penetrate the endothelial layer; i.e., diapedesis occurs, and become macrophages [106]. Macrophages target Ox LDL for phagocytosis and become foam cells, the accumulation of which causes the formation of fatty streaks. The foam cells initiate the production of transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) in the vascular system [107, 108]. These growth factors promote the change of vascular SMCs from a contractile to a synthetic phenotype. SMCs migrate from the media layer to the intima, where they secrete a complex extracellular matrix to form a fibrous cap around the lipid core to stabilize the plaque [109]. The proliferation of SMCs leads to neointima hyperplasia. Thus, the vessel becomes narrowed and the blood flow profile alters, further aggravating endothelial dysfunction (**Figure 4**).

**15**

*Nitric Oxide and Oxidative Stress-Mediated Cardiovascular Functionality: From Molecular…*

In fact, disturbed blood flow at arches, branches, or bifurcations is always associated with the early appearance and fast development of atherosclerotic lesions. Blood flow influences ECs' gene expression through "shear-stress response elements" in the promoters of atherosclerosis relevant genes and "mechanotransducers" that can sense the force and transduce mechanical signal into biochemical events within the cell. Overall, in steady laminar flow, ECs express more antithrombotic, anti-inflammatory, and antioxidant proteins, such as eNOS, cyclooxygenase-2 (COX-2), and manganese-dependent superoxide dismutase (SOD) [110], while in turbulent flow, ECs show atheroprone phenotypes, which activate NF-κB pathways to promote the expression of cytokines and cell adhesion molecules [107]. Two highly differentially expressed transcription factors, zinc finger transcription factor Kruppel-like factor 2 (KLF2) and nuclear factor erythroid-2-related factor-2 (Nrf2), were identified by comparing endothelial gene expressions under different hemodynamic patterns [111]. KLF-2 maintains endothelial homeostasis at least in part by inhibiting local inflammation and restoring NO levels. Overexpression of KLF-2 blocks IL-1β-induced inflammation through inhibiting VCAM-1 and E-selectin expression to disturb the adhesion of immune cells [112]. In addition, it upregulates eNOS expression to improve vascular tones. Nrf2 is responsible for regulating redox-related genes (heme oxygenase 1, ferritin heavy chain, NADPH dehydrogenase quinone 1, and thioredoxin reductase) to maintain vascular redox balance in laminar flow [111]. Remarkably, it has been shown that KLF2 and Nrf2 work synergistically to integrate atheroprotective signals and active antioxi-

dant responses, which may be a promising therapeutic strategy for CVDs.

To counteract the effect of excessive ROS and control CVD symptoms, introducing antioxidative mechanisms is an effective method (**Figure 5**). Increasing enzymes that can eliminate ROS is a commonly used strategy. For example, superoxide can be eliminated by dismutation of two superoxide molecules by SOD to O2 and H2O2 [113]. H2O2 can undergo decomposition under the regulation of catalase and peroxiredoxin to oxygen and water [80, 114]. The thiol group in peroxiredoxins

**5.3 Antioxidant mechanisms in nitroso-redox balance**

*DOI: http://dx.doi.org/10.5772/intechopen.82556*

*5.2.2 Hemodynamics and atherosclerosis*

*NO's role in the initiation and progression of atherosclerosis.*

**Figure 4.**

*Nitric Oxide and Oxidative Stress-Mediated Cardiovascular Functionality: From Molecular… DOI: http://dx.doi.org/10.5772/intechopen.82556*

**Figure 4.** *NO's role in the initiation and progression of atherosclerosis.*

#### *5.2.2 Hemodynamics and atherosclerosis*

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

superoxide before it initiates any cell response [101].

mice, tyrosine nitration of the voltage-gated K<sup>+</sup>

cardiomyocyte model [104].

*5.2.1 Inflammatory mechanism of atherosclerosis*

**5.2 Atherosclerosis**

(RyRs) [26]. Quantitatively, when three thiols per subunit of RyR channels are nitrosylated, the process is reversible. However, if six or more thiols per subunit are nitrosylated, irreversible Ca2+ ion release occurs and can be detrimental to the cardiac muscle [26]. In addition, when too much NO is generated during inflammation or sepsis, NO may cause hypovolemia due to its excessive vasodilation effect [83]. Furthermore, upregulation of iNOS in ECs reduces the availability of BH4 to eNOS, intensifying eNOS uncoupling and superoxide generation [83]. Thus, the physiological role of NO can be attenuated by ROS, because NO is quickly consumed by

When NO collides with superoxide, peroxynitrite (ONOO<sup>−</sup>) is formed, causing nitrosative stress. The chemical reaction is very fast and deleterious [98]. ONOO<sup>−</sup> is a very strong oxidant. It reacts with proteins through tyrosine and tryptophan residues to form nitrotyrosine and nitrotryptophan, respectively [80, 98]. In diabetic

altered its dilation function, a possible mechanism of the progression of coronary artery disease [102]. Tyrosine nitration was also observed in cardiac myocytes desmin, myosin heavy chain, α-actin, and microtubules. These proteins play pivotal roles in maintaining cell morphology and cardiac contractility [98]. When free nitrotyrosine was incorporated into the carboxyl terminus of α-tubulin in microtubules, altered microtubule organization and redistribution of the motor cytoplasmic protein dynein were observed [103]. Protein activity can also be impaired by oxidation of thiols to disulfide bond by ONOO<sup>−</sup> [98]. In addition, ONOO<sup>−</sup> also reacts with lipids to yield nitrated lipids to promote atherosclerosis, and with nucleic acids via guanine and the sugar phosphate backbone to damage DNA [98]. On the other hand, low concentrations of ONOO<sup>−</sup> (10–200 uM) is associated with tyrosine kinase-dependent signaling. ONOO<sup>−</sup> has been shown to activate tyrosine phosphorylation and trigger glycolysis [98]. Another example involves MAPK pathway, where ONOO<sup>−</sup> activates Raf-1 kinase. The MAPK pathway is closely associated with anti-apoptosis and cardiac hypertrophy in the cultured

Atherosclerosis is characterized by the formation of plaques that reduce the lumen

of arteries and consequently interfere with blood flow and tissue perfusion. The plaque consists of the lipid core and fibrous cap. In patients with hypercholesterolemia, ROS and RNS oxidize low-density lipoprotein (LDL) [105]. Oxidized LDL (Ox LDL) initiates a cascade of events that alters the endothelial permeability and leads to insudation of the lipoprotein in the arterial wall. Stimulated by atheroprone signals, ECs express selectins and vascular cell adhesion molecule (VCAM-1) to attract circulating blood monocytes. Monocytes penetrate the endothelial layer;

i.e., diapedesis occurs, and become macrophages [106]. Macrophages target Ox LDL for phagocytosis and become foam cells, the accumulation of which causes the formation of fatty streaks. The foam cells initiate the production of transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) in the vascular system [107, 108]. These growth factors promote the change of vascular SMCs from a contractile to a synthetic phenotype. SMCs migrate from the media layer to the intima, where they secrete a complex extracellular matrix to form a fibrous cap around the lipid core to stabilize the plaque [109]. The proliferation of SMCs leads to neointima hyperplasia. Thus, the vessel becomes narrowed and the blood flow profile alters, further aggravating endothelial dysfunction (**Figure 4**).

channels in the vascular SMCs

**14**

In fact, disturbed blood flow at arches, branches, or bifurcations is always associated with the early appearance and fast development of atherosclerotic lesions. Blood flow influences ECs' gene expression through "shear-stress response elements" in the promoters of atherosclerosis relevant genes and "mechanotransducers" that can sense the force and transduce mechanical signal into biochemical events within the cell. Overall, in steady laminar flow, ECs express more antithrombotic, anti-inflammatory, and antioxidant proteins, such as eNOS, cyclooxygenase-2 (COX-2), and manganese-dependent superoxide dismutase (SOD) [110], while in turbulent flow, ECs show atheroprone phenotypes, which activate NF-κB pathways to promote the expression of cytokines and cell adhesion molecules [107].

Two highly differentially expressed transcription factors, zinc finger transcription factor Kruppel-like factor 2 (KLF2) and nuclear factor erythroid-2-related factor-2 (Nrf2), were identified by comparing endothelial gene expressions under different hemodynamic patterns [111]. KLF-2 maintains endothelial homeostasis at least in part by inhibiting local inflammation and restoring NO levels. Overexpression of KLF-2 blocks IL-1β-induced inflammation through inhibiting VCAM-1 and E-selectin expression to disturb the adhesion of immune cells [112]. In addition, it upregulates eNOS expression to improve vascular tones. Nrf2 is responsible for regulating redox-related genes (heme oxygenase 1, ferritin heavy chain, NADPH dehydrogenase quinone 1, and thioredoxin reductase) to maintain vascular redox balance in laminar flow [111]. Remarkably, it has been shown that KLF2 and Nrf2 work synergistically to integrate atheroprotective signals and active antioxidant responses, which may be a promising therapeutic strategy for CVDs.

#### **5.3 Antioxidant mechanisms in nitroso-redox balance**

To counteract the effect of excessive ROS and control CVD symptoms, introducing antioxidative mechanisms is an effective method (**Figure 5**). Increasing enzymes that can eliminate ROS is a commonly used strategy. For example, superoxide can be eliminated by dismutation of two superoxide molecules by SOD to O2 and H2O2 [113]. H2O2 can undergo decomposition under the regulation of catalase and peroxiredoxin to oxygen and water [80, 114]. The thiol group in peroxiredoxins

#### **Figure 5.**

*Maintenance of redox balance in the cardiovascular system.*

consumes H2O2 to form sulfenic acid, then subsequently disulfide bond [115]. Glutathione (GSH) peroxidase 1 uses the similar mechanism to inactivate H2O2, superoxide, and ONOO<sup>−</sup> in the presence of the tripeptide compound GSH. A prospective cohort study showed that reduced levels of GSH peroxidase 1 were associated with increased mortality in coronary disease patients [116].

Another effective antioxidative method is to protect redox-sensitive molecules from being oxidized. In the body, the thiol group on GSH can form reversible mixed disulfide bonds with cellular proteins under oxidative stress conditions. These disulfide bonds can be broken by the enzyme glutaredoxin when the surrounding cell environment reverts back to its normal state [80, 117]. The addition of scavengers to directly remove ROS/RNS can also restore the nitroso-redox balance. An example is the elimination of superoxide by ascorbic acid (vitamin C) [113]. By limiting superoxide, other reactive species can also be repressed, such as • OH and ONOO<sup>−</sup>. This may explain the success of the clinical trial of combining nitrate drug isosorbide dinitrate with hydralazine, a NADPH oxidase inhibitor, where heart failure was reduced by 45% [118]. By inhibiting superoxide generation from NADPH oxidase, ONOO<sup>−</sup> level may be reduced and NO function preserved.

The high concentrations of NO can be controlled through scavenging NO via oxyhemoglobin in red blood cells and myoglobin in the skeletal and heart muscle. These two proteins react with NO to form nitrate, which is considered as the primary method for inactivating NO in the cardiovascular system [119]. Hemoglobin and myoglobin can also scavenge ONOO<sup>−</sup> by their metal centers, generating nitrate from the reactions [120].

#### **6. Conclusions and future outlooks**

We briefly reviewed the molecular mechanisms of muscle contraction and relaxation in the cardiovascular system and highlighted the importance of physiological and pathological effects of NO and oxidative stress. NO and ROS both determine the structural integrity and functionality of the cardiovascular system. The cardiovascular system not only nourishes cells, but also provides paths for immune response and systematic signaling. Drugs are transported by this system to the correct site for metabolic reactions. Tissue regeneration also relies on a healthy

**17**

**Author details**

**Conflict of interest**

Houghton, MI, USA

Chengdu, China

Weilue He1

provided the original work is properly cited.

\*, Maria Paula Kwesiga1

\*Address all correspondence to: weilueh@mtu.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Biomedical Engineering, Michigan Technological University,

2 Rehabilitation Medicine Center, West China Hospital, Sichuan University,

, Eyerusalem Gebreyesus1

and Sijia Liu<sup>2</sup>

*Nitric Oxide and Oxidative Stress-Mediated Cardiovascular Functionality: From Molecular…*

cardiovascular system. Therefore, to maintain, the homeostasis of the cardiovascular system is essential for overall health. Unfortunately, with aging, both cardiac function and cardiomyocyte number decline [121], and blood vessels undergo structural alterations [122]. Moreover, CVDs are also associated with other serious complications, such as diabetes, cancer, kidney failure, and inflammatory processes. Thus, multiple therapeutic strategies are needed to treat CVDs. According to 2011's American Heart Association's guidelines for preventing CVDs, therapeutic strategies include smoking cessation, blood pressure control, lipid management, physical activity programs, diabetes management, anticoagulation, dilation management, and depression prevention [3]. Besides traditional pharmaceutical management and surgeries, new perspectives to study, diagnose, and treat CVDs have also shown promising results, including development of biocompatible stents [123], stem cells therapies [124, 125], novel devices for mechanical thrombectomy [126], and inflammation management [127]. Although challenges still exist, the implementations of research findings from different disciplines in clinical trials will

allow us to better understand and control CVDs in the future.

The authors have declared that no conflict of interest exists.

*DOI: http://dx.doi.org/10.5772/intechopen.82556*

*Nitric Oxide and Oxidative Stress-Mediated Cardiovascular Functionality: From Molecular… DOI: http://dx.doi.org/10.5772/intechopen.82556*

cardiovascular system. Therefore, to maintain, the homeostasis of the cardiovascular system is essential for overall health. Unfortunately, with aging, both cardiac function and cardiomyocyte number decline [121], and blood vessels undergo structural alterations [122]. Moreover, CVDs are also associated with other serious complications, such as diabetes, cancer, kidney failure, and inflammatory processes. Thus, multiple therapeutic strategies are needed to treat CVDs. According to 2011's American Heart Association's guidelines for preventing CVDs, therapeutic strategies include smoking cessation, blood pressure control, lipid management, physical activity programs, diabetes management, anticoagulation, dilation management, and depression prevention [3]. Besides traditional pharmaceutical management and surgeries, new perspectives to study, diagnose, and treat CVDs have also shown promising results, including development of biocompatible stents [123], stem cells therapies [124, 125], novel devices for mechanical thrombectomy [126], and inflammation management [127]. Although challenges still exist, the implementations of research findings from different disciplines in clinical trials will allow us to better understand and control CVDs in the future.
