4 Review article

Pathophysiology of cardiovascular disease in diabetes

mellitus
Gerardo Rodriguez-Araujoa,b and Hironori Nakagamic

Diabetes mellitus elicits cellular, epigenetic, and Cardiovascular Endocrinology & Metabolism 2018, 7:4–9
post-translational changes that directly or indirectly affect Keywords: atherosclerosis, cardiovascular disease, cell signaling,
the biology of the vasculature and other metabolic systems cholesterol toxicity, diabetes mellitus, dyslipidemia, epigenetics,
glucose toxicity, inflammation, pathophysiology
resulting in the apparition of cardiovascular disease. In this
a
review, we provide a current perspective on the most recent Clinical Research Innovation, ProSciento Inc., Chula Vista, California, bGraduate
School, University of Arkansas for Medical Science, Little Rock, Arkansas, USA
discoveries in this field, with particular focus on and cDepartment of Health Development and Medicine, Osaka University
hyperglycemia- induced pathology in the cardiovascular Graduate School of Medicine, Osaka, Japan
system. We also provide perspective on the clinical Correspondence to Gerardo Rodriguez-Araujo, MD, PhD, Clinical Research
importance of molecular targeting of cardiovascular and Innovation, ProSciento Inc., 855 3rd Avenue, Suite 3340, Chula Vista,
CA 91911, USA
diabetes mellitus therapies to treat hyperglycemia, Tel: + 1 619 409 1269; e-mail: [email protected]
inflammation, thrombosis, dyslipidemia, atherosclerosis,
and hypertension. Cardiovasc Endocrinol Metab 7:4–9 Received 19 October 2017 Accepted 22 November 2017

Copyright © 2018 Wolters Kluwer Health, Inc. All rights

reserved.

Introduction mechanisms and molecular abnormalities. T2DM has

Diabetes mellitus (DM) often coexists with cardiovas- multiple cell-signaling pathways in cell growth, survival,
cular disease (CVD) in clinical practice, but the patho- and proliferation such as pAkt, endothelial nitric oxide
physiology of this comorbid condition could be rather synthase pathway, and AMP-activated protein kinase
confusing as the amount of scientific evidence is dis- pathways that could potentiate the development of CVD.
persed and has increased, especially in the last decade. In addition to this, glucose and oxidized lipids exert
important effects in tissues at the epigenetic level [5–7].
The strong link between these two diseases is evident.
It is noteworthy that some of these epigenetic adapta-
Patients with CVD share similar risk factors for DM onset
tions can even be passed down to several generations
such as unhealthy dietary and lifestyle habits, obesity,
[8–10].
smoking, etc., or already have DM (http://www.who.int/
mediacentre/factsheets/fs317/en/). Similarly, DM itself con- In this review, we provide a current perspective on the
stitutes a risk factor for CVD and its complications, such advances of such discoveries and for this purpose; we grouped
as myocardial infarction (MI), stroke, amputation, etc. [1]. them as CVD risk factors affecting the biology of patients
with pre-existing DM. We also provide a brief overview on
The mechanisms of the pathogenesis of CVD in diabetes
how cell-signaling pathology and post-translational changes in
are related to epigenetic, genetic, and cell-signaling
hypertension, dyslipidemia, inflammation, and hyperglycemia
defects in inter-related metabolic and inflammatory
result in the early appearance of CVD phenotypes and the
pathways. These metabolic defects (especially in the
opportunity for new therapies. In an attempt to explain the
endothelium, liver, skeletal muscle, and β cells) can be
major relevant pathophysiological pathways that are present
triggered by various environmental factors such as high
in DM that are related to CVD and their therapeutic impli-
caloric intake, smoking, glycation end-products, glucose
cations, we have listing them on the basis of their clinical
toxicity, and some medications [2]. It could be stated that
phenotype.
the expression of both type 2 diabetes mellitus (T2DM)
and CVDs is an idiosyncratic response to the environ-
Hyperglycemia
ment, guided by the biological capacity of cellular sys-
T2DM is considered a multifactorial disease that involves
tems in patients [3].
abnormalities in carbohydrate and lipid metabolism [11].
These idiosyncrasies are expressed differently among Its most evident manifestation is chronic hyperglycemia.
patients and populations [3]. Some patients may express Recent evidence shows that T2DM patients have defects
clear or mixed phenotypes of hyperglycemia, dyslipide- in epigenetic and post-translational modifications of the
mia, hypertension, inflammation, or thrombosis, which vascular architecture [2]. The multiple endometabolic
also represent risk factors for CVD [4]. Interestingly, all defects of diabetes impact behaviors such as overfeeding
of these clinical manifestations share similar cellular (leptin resistance or deficiency) as well as aspects of
2574-0954 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/XCE.0000000000000141

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 Pathophysiology of CVD in DM Rodriguez-Araujo and Nakagami 5

glucose and lipid metabolism such as cellular toxicity and inflammatory nuclear factors (NF-κB) feeding the
insulin receptor (IR) effects of palmitic acid and other chronic loop of persistent inflammation. In particular,
saturated fatty acids [12]. Leptin is a protein secreted by TLR-2 and TLR-4 affect the frequency, plaque size, and
white adipocytes and has the function of stimulating lipid content of atherogenic plaque and the expression of
satiety (postprandial) and increase energy expenditure by inflammatory genes and cytokines (IL-12, monocyte
binding its cognate receptor (leptin receptor B) [13]. chemoattractant protein-1, etc.) [22]. In this respect,
Mutations in either leptin protein (biologically inactive) colchicine, an anti-inflammatory agent, has been shown
or its receptor (defective activation) result in overfeeding to decrease IL-1b, MI, acute coronary syndrome, and
behaviors, leading to profound obesity phenotypes with noncardioembolic stroke in phase III studies [23,24].
the association of peripheral insulin resistance and Canakinumab, a monoclonal antibody against IL-1b, is
hyperglycemia [14]. another perfect example of an anti-inflammatory drug
that reduces recurrent CV events independent of lipid
Similarly, saturated fatty acids such as palmitic acid have
levels as shown in the CANTOS study [25].
been proposed as insulin desensitizers not just in per-
ipheral tissues but also in the hypothalamus. This dual For instance, circulating inflammatory factors can activate
effect leads to peripheral and central insulin resistance, potentially life-threatening cell signaling such as throm-
resulting in hyperglycemia and dysregulation of energy bosis by platelet activation of both classical and alter-
balance in the whole organism [14,15]. The chronicity of native pathways [26]. Platelets are easily activated and
the insulin resistance along with the effect of saturated can aggregate quite fast in response to such circulating
fatty acids, lipoproteins, leptin, and circulating proin- cytokines, especially in low-flow areas such as the cor-
flammatory cytokines translates into apoptosis of islet onaries, the lower extremities, the brain, etc. [26,27]. The
β cells [16]. As glucose is taken up poorly by cells in the occlusion or sub occlusion of these vessels can result in
organism, this causes postprandial glucose levels to infarctions or necrosis of important tissues such as the
remain consistently high for prolonged periods of time, brain and the heart, increasing the risk for stroke and MIs
resulting in glucose-related tissue toxicity [production of [28–30].
receptor for advanced glycation end-products (RAGE),
In vessels that have an atherogenic lesion, in addition to
endothelial dysfunction, histone hyperacetylation, DNA
the circulating inflammatory signals, local signals, along
methylation, etc.] [2]. This toxicity affects microvessels
with plaque erosion, partial, or total rupture, can trigger
and macro vessels (retinopathy, coronary arterial disease,
thrombosis in the atherogenic suboccluded area or distal
etc.), nerves (peripheral neuropathy), and nephrons
regions on that artery territory [29,30]. Infiltration of
(decreased glomerular filtration and microalbuminuria),
immune cells can be found in plaques and although these
with deleterious clinical consequences. IR agonists such
cells repair and replace tissue, its presence and the
as chaetochromin derivatives and monoclonal antibodies
release of inflammatory chemoattractive substances
with agonist activity on the IR have been reported to
worsen the thrombotic state and increase the risk of
improve IR responsiveness and Akt activations, respec-
further plaque core necrosis and plaque instability, with
tively, thus improving glucose metabolism at the cellular
the subsequent release of debris into the distal portions
level in patients with peripheral insulin resistance
of the artery lesion, a condition that worsens under low
[17,18].
shear stress conditions [31–33].
It is noteworthy that another less characterized player,
Chronic inflammation and thrombosis
RAGE, is implicated in deleterious effects on energy
Glucose toxicity by aldose reductase activation initiates
expenditure, weight gain, adipose tissue inflammation,
subsequent PKC-dependent nonosmotic nuclear factor
and insulin resistance together with a high-fat diet.
(NF)-κB activation, resulting in the production and
RAGE protects against high-fat diet-induced systemic
release of proinflammatory cytokines such as interleukin
inflammation and weight gain [34]. Also, elevated serum
(IL)-6, IL-12, IL-10, tumor necrosis factor-α, etc. [19,20].
RAGE of more than 838.19 pg/ml can double the risk for
Similarly, inflammation in adipose tissue leads to the
CV events in patients with pre-existing CVD (a compo-
release of adipocytokines such as adipsin, adiponectin,
site of MI, stroke, and CV death) [35].
leptin, tumor necrosis factor-α, and plasminogen activator
inhibitor I. The vascular redox state is affected by
transduction signal signals originating from inflammatory, Dyslipidemia and atherogenesis
obesity, and insulin-related pathways. Importantly, Dysplipidemia and obesity are often present in patients
adipose tissues can modify the secretory profile when with DM and can facilitate atherogenesis and athero-
sensing paracrine signals of cardiovascular (CV) oxidative sclerosis [36]. Fat droplets in cells, especially adipocytes,
stress or injury [21]. Such inflammatory signals can are essentially ‘packed energy’ that our body can use as a
transduce cellular signals in tissues such as fat, liver, fuel source in times of fasting or when there is a need for
muscle, heart, endothelium, etc., through toll-like extraphysical activity [37]. In contrast, carbohydrates are
receptor (TLR) signaling, which in turns activates metabolized into energy using aerobic or anaerobic

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6 Cardiovascular Endocrinology & Metabolism 2018, Vol 7 No 1

mitochondrial pathways. If all the elementary energy matrix metalloproteinase (MMP) protein-10, cysteine/gluta-
requirements of the cell are met, then lipids are synthe- mate transporter (SLC7A11), and MMP1 [49]. ILs and
tized from carbohydrates, a process called ‘de-novo metalloproteinases are closely related as they are both
lipogenesis’ [38]. Lipids can be stored and converted regulated by proinflammatory signals and participate in
back into burnable compounds (pyruvate) within the cell vascular remodeling, particularly in plaque progression and
[37]. Lipids can themselves be a ‘source of energy’ in plaque instability [50,51]. MMP inhibitors have been used
times of fasting that, along with their high affinity to cell to stabilize plaques, but there is a need for more selective
membranes, can access the cells with minimum effort targeting of MMPs as broad-spectrum inhibitors exert dual
(vectors-exosomes) [37,39]. However, the distribution of effects on the plaque [51].
lipids is aided by proteins as their physicochemical
Hyperglycemia also induces DNA methylation of important
properties allow them to remain in the circulatory system,
genes for glucose metabolism, G-coupled protein receptors
avoiding early absorption [40]. The synthesis of those
(GPRs), and insulin growth factor proteins such as ABCC11,
proteins is mainly orchestrated by the liver. Those pro-
ADAD1, ADAM8, BCL3, CCDC61, CEP120, CSF1R, CSTL1,
teins are categorized according to their molecular density
CTTNBP2NL, EGLN3, ENOX1, ERAS, FAM107A, FASLG,
into very low-density lipoprotein (LDL), LDL, and high-
GADD45B, GNG2, GPR39, GPR62, GRK7, HMGB2,
density lipoprotein. Along with triglycerides, which are
HNRNPL, HYOU1, and IGFBPL1 [49]. Gene expression
clusters of lipids, lipoproteins travel along the circulatory
and suppression persist for up to 6 days in the endothelium
system to distal organs and tissues [40].
after the hyperglycemic episode in vitro [2]. Here is the
Chronic high levels of atherogenic LDL cholesterol importance of novel GPR agonists which currently are
along with increased non-high-density lipoprotein C and underway in an effort to improve GPR signaling in tissues
ApoB values in patients have been related to the pro- and its metabolic benefits in patients with diabetes [52,53].
gression of atherogenesis [41]. Oxidation of low-density
Other epigenetic mechanisms such as microRNAs (miR)
lipoprotein (oxLDL) is an important condition that
can regulate gene expression post-transcriptionally,
represents oxidative stress and increases the atherogenic
directly exert their effects in signal pathways, and reach
and inflammatory properties of LDL [42]. In addition,
other cells when included in extracellular vesicles called
elevated serum levels of oxLDL are associated with the
‘exosomes’ [54]. miR-941, miR-208b, miR-197, and miR-
incidence of coronary disease [42,43]. Therefore, a logical
223 have been found to have diagnostic value in pre-
therapeutic target is the reduction of the LDL choles-
dicting CV events or CV death [55–57]. miR-126-5p has
terol by statins or by the novel proprotein convertase
been associated inversely with the complexity of CAD
subtilisin/kexin type 9 inhibitors. Statins inhibit the
with low serum levels in multivessel disease and high
production of cholesterol by inhibiting the transformation
SYNTAX scores in patients with stable angina [58]. Some
from hydroxymethylglutaryl-coenzyme A into mevalonic
epigenetic therapies are underway as potential antith-
acid (primitive fatty acid) [44]. In contrast, proprotein
rombotics such as miR-19b for use in patients with
convertase subtilisin/kexin type 9 inhibitors increase
unstable angina [59]. Also, a bigger epigenetic factor,
LDL-receptor density on the cell surface, facilitating
long noncoding RNAs in exosomes, such as exosomal
LDL intake by the cell and decreasing circulating LDL,
long noncoding RNA-growth arrest-specific 5 (long
thereby facilitating plaque regression as reported recently
noncoding RNA GAS5), can increase the apoptosis of
in the GLAGOV study [45].
macrophages and endothelial cells in atherosclerosis [60].
Concurrently, hyperglycemia contributes toward the
development of atherosclerosis and arterial stiffness [46]. Hypertension
Chronic damage to the endothelium and the effects of The renin–angiotensin–aldosterone system has been
inflammatory cytokines on endothelium play important proposed as a feasible model to explain secondary
roles in the genesis and stability of the plaque. The cellular hypertension as the cause of primary hypertension is
mechanisms of media thickening and proliferation, pre- unknown [61]. Inflammatory cytokines have a major
sence of endothelium- adhesion molecules (vascular cell impact on the endothelium by affecting the capacity of
adhesion molecule 1 and intercellular adhesion molecule 1), energy metabolism (mitochondrial dysfunction) and the
and infiltration of macrophages in the subintima are regu- release endothelial nitric oxide synthase, which is an
lated by epigenetic mechanisms and posttranslational important vasodilator, thus affecting vascular relaxation
modifications [47,48]. Hyperglycemia induces hyper- and inducing arterial stiffness [62–64]. These inflamma-
acetylation of histone H3K9/K14 in 88 genes codifying for tory cytokines chemoattract macrophages and lympho-
diabetes, 52 genes for hypertension, and 84 genes for CV cytes, which can produce and release reactive oxygen
disorders among other diseases [49]. It is particularly note- species and angiotensin II (AngII) [62,63]. Reactive
worthy that hyperacetylation of the histone H3K9/K14 in oxygen species activates NF-κB signaling, amplifying the
the endothelium results in the expression of important vicious cycle of local inflammatory response, and AngII
glucose metabolism and metalloproteinases regulating increases the blood flow by inducing constriction of the
genes such as heme oxygenase 1 (HMOX1), IL-8 precursor, media of arteries, thereby increasing blood pressure [65].

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 Pathophysiology of CVD in DM Rodriguez-Araujo and Nakagami 7

As this inflammatory stage is chronic, AngII can con- renin–angiotensin–aldosterone system, as it may be more
sistently and continuously induce an increase in blood clinically relevant than the sympathetic pathway [70].
pressure. This high-flow system induces the develop-
ment of media hypertrophy, reducing even more the
Discussion
arterial lumen, which in turn increases resting blood
The optimal balance between genes codifying for epige-
pressure values [66,67]. Unchecked stages of this condi-
netic modulators and associated proteins required for the
tion may result in the onset of secondary hypertension
transcription of these modulators can be affected by cel-
and the need for a medical intervention with lifestyle lular toxic products such as glucose itself and glycation
changes and antihypertensives [67]. end-products leading to transcriptional stages of inflam-
The persistence of a high-flow system together with mation (oxidative stress, cytokine production, and release
inflammation, dyslipidemia, and hyperglycemia increases and apoptosis), endothelial dysfunction (decrease in nitric
the risk of atherogenic plaque erosion or rupture, oxide production and release of AngII), and down-
hemorrhage (especially microcirculation), and thrombo- regulation of GPR density. oxLDL plays a role in the
sis [68]. pathogenesis of CVD by desensitizing the IR pathway and
IR-dependent glucose uptake, thus reinforcing hypergly-
Sympathetic regulation of blood pressure by catechola- cemia and its toxic effects in cells. Another CVD risk factor
mines also plays an important role in the presence and described in this review is hypertension, triggered by
persistence of hypertension [61,69]. Renal denervation inflammatory signals, together with the inability to control
was proposed to treat uncontrolled hypertension without vascular relaxation by nitric oxide and angiotensin, both of
relevant and consistent results in the SYMPLICITY which are endothelium-release-dependent factors. Taken
HTN-3 trial, pointing to the utility of targeting together with atherovascular lesions, this could result in a

Fig. 1

Antiinflammatory
Atherogenesis Drugs
CV Events and plaque
(MI, Stroke, CV
Death, etc.)
inestability Inflammation Energy Expenditure &
Overfeeding Behavior

beta- cell IL-12, MCP-1 Leptin Resistance

apoptosis
Recombinant Insulin
Insulins Dyslipidemia
sRAGE
Fatty Acids- Hypothalamus
Statins Palmic Acid
AGE
Hyperglycemia
Glucose PCSK-9i
Increase LDL-R Leptin
density

FGF/EGF/RAGE
Hypertension Poor Glucose Uptake Insulin Receptors
LDL-R Receptor
IL Receptors Released cytokin

Aldose
GPR agonist reductase
Arterial pAkt ERK-MAPK
PKC
Stiffness GPRs
DNA methylation: Mitochondrial
ABCC11, ADAD1, ADAM8,GNG2, Stress &
GPR39, GPR62, GRK7, HMGB2, Dysfunction
HNRNPL, HYOU1, IGFBPL1, etc .
ARB, ACEi RAAS Low density of GPRs
Adipsin
H3K9/H14 Hyperacetylation Adiponectin
HMOX-1
Leptin
MMP-10
SLC7A11 NFk-b PAI-1
MMPi eNOS MMP-1 IL-1
+ IL-6
88 genes DM, 52 genes IL-10
HTN, 84 genes CVD IL-12
H3K9/H14 TNF-alpha

Cellular and clinical implications in DM that precipitate CVD and their importance for therapeutics.

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8 Cardiovascular Endocrinology & Metabolism 2018, Vol 7 No 1

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