CVD &

OXIDATIVE
STRESS
Basith Halim
Marissa Putri Pratama
Nabila Viera Yovita
Abstract

• Oxidative stress  the generation of cellular damage & the involvement in several
signaling pathways in its balanced normal state.

• Relationship between CVD and oxidative stress and the most prominent molecules 
important role in CVD pathophysiology.

• Novel therapies, recently proposed ROS biomarkers  how ROS are contributing to
the pathophysiology of CVD
INTRODUCTION
Introduction

• In 1985, Sies, oxidative stress  disturbance in the balance of reactive oxygen species
(ROS) and antioxidants.

• Now oxidative stress  transient or permanent perturbation in the ROS balance-state

generates physiological consequences within the cell, for which the precise outcome
depends on ROS targets and concentrations
Introduction

• ROS  Guanylate cyclase activation, nervous system physiology regulation,

immune cell differentiation and response regulation, the mediation of
phosphatases, kinases, growth factor signaling pathways and stem cell

• ROS  Xenobiotics, such as radiation, drugs, habits like smoking, as well as

environmental agents

• ROS  Mitochondria, endoplasmic reticulum, peroxisomes and enzyme systems,

involving for example NADP oxidases and xanthine oxidase

• ROS  superoxide (-O2), hydroxyl radicals (HO), hydrogen peroxide (H2O2),

singlet oxygen (O2), peroxynitrite (OONO-) and nitric oxide (NO)

• ROS  cancer, neurodegenerative diseases, diabetes and cardiovascular

diseases (CVD)
CVD Highlights and
Their Relationship
with Oxidative Stress
CVD Highlights and Their Relationship with Oxidative Stress

• WHO  CVD is the leading causes of death worldwide

• CVD  31% of deaths globally in 2013, 17.5 million deaths per year.

• The 2016 CVD statistics update by AHA one in three persons in the U.S. was
affected with CVD  $863 billion in 2010, expectation of $1044 billion in 2030
CVD Highlights and Their Relationship with Oxidative Stress

Factor Risk, AHA :

• 2011 (PE) as a risk factor of CVD.

• obesity, diabetes, tobacco smoking, a sedentary and unhealthy lifestyle, family history,
genetic predisposition and oxidative stress.

• Atherosclerosis  the hardening and narrowing of arteries that consequently reduces

the flow and delivery of blood and oxygen throughout the body.
CVD Highlights and Their Relationship with Oxidative Stress
ROS Types and
Principal Sources in
CVD
ROS Types and Principal Sources in CVD
ROS Types and Principal Sources in CVD
MITOCHONDRIAL-ROS
 o Mitochondria are nowadays considered as the major source of ROS in most cells
MITOCHONDRIAL-ROS

o The most abundant damaging ROS in vascular tissue is –O2 (superoxide) and ROS- –O2
generation within mitochondria, mainly from the electron transport chain (ETC) pathway

o Mitochondrial-ROS (mtROS) is involved in several pathways, plays a role in the innate

immune response (bactericidal effector)

o Close relation between mtROS and endothelial dysfunction  through influence of mtROS
and –O2 production stimulation in endothelial cells

o NO concentration is decreased in the presence of –O2  reaction between the two produces
OONO- (peroxynitrite)  can generate irreversible cellular damage
MITOCHONDRIAL-ROS

Diabetes, hypertension and aging have

shown association between NOXs and
mitochondria

Mitochondria and NOX both predominate

as major ROS sources in diabetes,
hyperglycemia is associated with
mitochondria-NOX-ROS crosstalk

DM type 2 has a causal link with CVD,

sulfonylurea use in CVD showed link to K ATP
channels
Channel opening inhibition & over-induction
vascular complications, sudden cardiac dea

In a diabetic state, a predominantly

decreased function of KATP channels
have been observed  due to ishemic
preconditioning  myocard infarct
MITOCHONDRIAL-ROS

Within mitochondria, 2 CIII-ROS has cardio- Inhibition of other

sources of ROS production protective functions, CI-ROS mitochondrial systems that
predominate in the ETC: results in damage and are involved in the
complex I (CI) and complex association with CVD -> not production of ROS eg.
III (CIII)  stimulate the considered as dominant monoamine oxidase (MAO)
opening of pores (mPTP and source of ROS under  associated with
KATP) normal/healthy conditions, protection against I/R
but majo mitochondrial injury, heart failure and
source of electron leakage
NADPH OXIDASES
 o NOX family enzymes are major contributors of ROS production. NOX1, NOX2, NOX4 and
NOX5 are complexes that assemble in the membrane, expressed in vascular tissue with
apparent only purpose of producing ROS.
NADPH OXIDASES

NOX Production site

NOX 1 Vascular smooth musle cells (VSMCs)
NOX 2 Cardiomyosites, fibroblast
NOX 4 Cardiomyosites, fibroblast,
Vascular smooth musle cells (VSMCs)
NOX 5 Vascular smooth musle cells (VSMCs)
*NOX enzymes are characterized by –O2 production, but NOX4 is the exception to the
rule due to its predominant H 2O2 generation
**NOX4 has been shown to increase ROS production while induced by transforming
growth factor-ß
***NOX4 function is associated with vascular injury, that responds in later stages, has a
protective role in HT disorders, reduce basal blood pressure – linked to H 2O2
production.
 NOX-ROS has a dual role: H2O2 generated through NOX disrupts tyrosine phsophorylation signaling by thiol
oxidation of p-Tyrosine  conversion to DOPA protein  promote disruption of networks  alteration of
NADPH OXIDASES

biological process.

In the presence of bacteria, H2O2 interferes with bacterial tyrosine kinase signaling by decreasing virulent
damage.
All NOX-ROS triggers lead to endothelial dysfunction, it
can easily interact with other ROS resources and these
Disturbance of NOX enzymeswith
are each other 
associated leading
with to a never
endotheliat ending oxidative
dysfunction, atherosclerotic plaque formation, LDL
stress state
oxidation, macrophages and neutrophil recruitment, etc CVD genesis and progression

RISK FACTORS causing NOX PRODUCTION

Exogenous

Endogenous `` 1. Pro-inflamatory molecules 2. Growth Factor 3. PDGF hormones (insulin,

Ang II)
NADPH OXIDASES

Cardiovascular dysfunction High glucose 

& atherosclerosis are increase
related with increased cardiomyocyte NOX4
expression of NOX 2, 4 and production  cardiac
5 at early stages only damage

NOX1 is activated by a Other CVD phenotypes eg.

diabetic state  Pulmonary artery HT and
hyperglycemia induces atrial fibrillation have been
Ang II & PDGF related to NOX activity 
production  vascular excess ROS and decrement
dysfunction & NOX1-ROS of NO in myocardial tissue.
production, HT, and NOXsROS involved in
atherosclerosis. induction phase of AF
development
XANTHINE OXIDASE
 XO
XANTHINE OXIDASE

First biological mechanism

identified as producer of ROS.
Apart from its pathological
function, can confer protection
from pathogen infections.

XO-ROS production linked to

endothelial dysfunction mainly
URIC ACID due to reaction of –O2 & NO 
Common factor observed in OONO-  cellular damage
CVD patients  UA
pathophysiology in CVD still
not elucidated though
xanthine oxyreductase
suggested important.
Excess of UA
Xanthine dehydrogensae
(XDH) & xanthine oxidase (XO) In certain CVD states (CHF,
reduce hypoxanthine and CAD) can function as marker of
xanthine to UA. upregulated XO activity.
XDH uses NAD+ as electron Inhibition through allopurinol tx
receptor  triggered by only showed improvement in
hypoxia, cell apoptosis, patients with this characteristic
LIPOXYGENASE
(LO)
LIPOXYGENASE

• Lipoxygenase (LO): family of enzymes metabolize fatty acids into

bioactive lipid mediators that exert potent actions on inflammatory
reactions.
• 5-LO and 12/15-LO display high correlation with CVD genesis.
• 5-LO can be upregulated by cytotoxicity and oxidative stress (NOX or
mitochondrial ROS).
• Arachidonic acid + 5-LO  5-HETE and LTA4, both are lipid mediators.
• LTA4  LTB4, LTC4, LTD4, LTE4  activate endothelial cells,
macrophages, neutrophils, mast cells, foam cells, T-cells  cytokines
and metalloproteinases.
LIPOXYGENASE
LIPOXYGENASE

• 12/15-LO involved in increased inflammation and oxidative stress

and plays a role in atherosclerosis development.
• AA + 12/15-LO  12-HPETE and 15-HPETE.
• 12/15-LO over expression associated with high production of pro-
inflammatory cytokines, IL-6, and TNF-α.
• 12/15-LO activity is characterized by oxygenation of LDL and NOX-
ROS production.
LIPOXYGENASE

• ROS and 15-LO upregulation  apoptosis  damage in pulmonary

artery  pulmonary hypertension.
• AA + 15-LO  15-HETE  enhance mitochondrial electron transport
chain and NOX4-ROS generation induce endothelial cell migration
 vascular remodelling
MYELOPEROXIDASE
(MPO)
MYELOPEROXIDASE

• MPO is a leukocyte-derived enzyme that catalyzes the formation of a

number of reactive oxidant species.
• MPO derived oxidants contribute to tissue damage during inflammation.
• MPO are present in high quantities in neutrophils and to a lower extent
in monocytes.
• MPO  HOCL- and HOSCN. Have bactericidal effect.
MYELOPEROXIDASE
MYELOPEROXIDASE
PHARMOCOLOGICAL
APPROACH
PHARMACOLOGICAL APPROACH

• Main goal: lower BP, regulate lipid content, and prevent formation of
atherosclerotic plaque.

Statin ARBs Antiplatelet

• inhibits HMG CoA • enhancement of • COX inhibitor

reductase plasma levels of • Adenosine
pathway  angiotensin II  diphosphate
enhance the stimulate receptor blocker
expression of angiotensin II type • GP IIb-IIIa inhibitor
endothelial NOS II receptors  NO • Thrombin receptor
production antagonist
THERAPEUTICS
CHALLANGE
THERAPEUTIC CHALLANGE

• Caloric restriction has been shown to reduce –O2 generation,

potentiating NO bioavailability  decreasing endothelial dysfunction.
• Nicotinamide mononucleotide supplementations was shown to
normalize superoxide production and increase antioxidant MnSOD
availability, and also ameliorates vascular changes that produce
arterial stiffness.
• Trehalose supplementation improves resistance artery endothelium-
dependent dilatation, increase NO generation and availability within
the cells.
• Antioxidant mitoquinone (MitoQ) increases leukocyte velocity 
decresing its flux and adhesion to endothelium  avoiding oxidative
stress and inflammation
THERAPEUTIC CHALLANGE

Phytochemicals from:

• Fruits (polyphenols: anthocyanins, ellagitannins, catechins, tannins)

• Vegetables (flavonoids: quercetin, lycopene)
• Spices (piperine, safranal)
• Other sources (epicathechin, 3-gallate, epic-gallocatechin)
THERAPEUTIC CHALLANGE

• Vitamin precursors, such as carotenes, vit A, E, and C, as well as

selenium, zinc, magnesium, and resveratrol are know to have
antioxidant properties.
• Pistachios and almonds reduce lipid peroxidation and have protective
effect against oxidative stress in subjects with DM and metabolic
syndrome.
CONCLUSION
CONCLUSION

• CVD pathogenesis: inflammation, oxidation, adhesion

molecules, LDL, endothelial tissue, leucocytes  endothelial
dysfunction.
• Discrepancies and inconsistencies among the different
research studies.
• Larger studies needed to describe more reliable biomarkers
that can be targeted and potentially used in therapies.