Regulated RIPK3 Necroptosis is Produced in Cardiovascular Tissues and Cells in
Dietary Magnesium Deficiency: Roles of Cytokines and Their Potential
Importance in Inflammation and Atherogenesis
Burton M Altura1-6*, Nilank C Shah1,5, Gatha J Shah1,5 and Bella T Altura1,3-6
1Department of Physiology and Pharmacology, SUNY Downstate Medical Center, Brooklyn, New York, USA
2Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, USA
3The Center for Cardiovascular and Muscle Research, SUNY Downstate Medical Center, Brooklyn, New York, USA
4The School of Graduate Studies in Molecular and Cellular Science, SUNY Downstate Medical Center, Brooklyn, New York, USA
5Bio-Defense Systems, Inc, Rockville Centre, New York, USA
6The Magnesium for Health Foundation, California, USA
- *Corresponding Author:
- BM Altura
Department of Physiology and Pharmacology
SUNY Downstate Medical Center, Brooklyn, NY 11203, USA
E-mail: [email protected]
Received date: May 11, 2017; Accepted date: May 30, 2017; Published date: June 05, 2017
Citation: Altura BM, Shah NC, Shah GJ, Altura BT (2017) Regulated RIPK3 Necroptosis is Produced in Cardiovascular Tissues and Cells in
Dietary Magnesium Deficiency: Roles of Cytokines and Their Potential Importance in Inflammation and Atherogenesis. J Med Surg
Pathol 2:e104. doi: 10.4172/2472-4971.1000e104
Copyright: © 2017 Altura BM et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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An earlier report from our research group, suggested a progressive
dietary and/or a metabolite-induced loss of magnesium (Mg) during
early developmental stages of life, particularly in coronary arteries
could lead to coronary arterial spasm (CAS), ischemic heart disease
(IHD), and sudden cardiac death (SCD) . After our first report, a
number of clinical studies have been reported, in support of our
hypothesis, at least in adults [2-7]. Autopsies driven results from
children who died due to accidental causes have been reported to
which show early signs of atherogenesis (i.e., fatty streaks on the walls
of the aorta and carotid arteries in young children as early as six years
of age) . Intriguingly, atherosclerosis is the prime cause of
premature death in developing countries and even in United States,
which further has been assumed to play a major role in the etiology of
hypertension and strokes.
Irregularities in daily-diets are known to induce inflammatory lesions, which are believed to mediate the initiation process of
atherogenesis. Further, the same diet disturbances have been reported
to promote lipid deposition and accelerate the growth and
transformation of the smooth muscle cells in the vascular walls [9-14].
Lack of dietary Mg accumulation has been experimentally
demonstrated to cause hypertension [11-13], atherogenesis [11,15-20],
and strokes [11,19,21-23]. On the other hand, hypermagnesemic diets have been reported to ameliorate hypertension, atherogenesis, stroke,
and normalize the levels of certain inflammatory responses
[11-15,19-32]. As per Western diet concerns, subnormal dietary intake
of Mg is reported among the majority of the American population and
the Mg shortfall level ranges from between 65 to 275 mg of Mg/d in
different demographic regimes [11,14,24,26,33-36]. In recent years, the
statistical data of USA NHANES indicates that, near about 65% of the
American population is suffering from Mg deficiency . Moreover,
several epidemiologic studies from North America and Europe have
shown that, both children and adults were low in the Mg content,
while they were consuming Western-type diets and surprisingly a large
portion of the low Mg individuals were in the gestation period
(<30-50% of the RDA for these populations) [11,37-42].
Improvisation in the specific Mg2+-ion selective electrodes, by our
research group demonstrated for the first time that, patients suffering
from hypertension, IHD, cardiac failure, renal-induced vascular diseases, diabetic vascular disease, and strokes as well as atherogenesis
exhibit significant reductions in serum/plasma/whole blood levels of
ionized, but not necessarily total, blood levels of Mg
[11,18,19,22-24,41-62]. Even in rabbit and rat model systems our
group has shown that, dietary deficiencies of Mg results in vascular
remodelling (i.e., arteriolar wall hypertrophy and alterations in the
matrices of the vascular walls), which was concomitant with
atherogenesis, high blood pressure, and microvascular vasospasm
[11-13,16,18,19,22,24,34,42,57-61]. Similar study outcomes also have
been reported by others supporting the contention of our findings
During the process of atherosclerosis, it has been shown that, the
lipid-rich plaques on the blood vessel intimas are complexed with
macrophages, lipids, T lymphocytes, and cholesterol crystals .
Large necrotic cores are the major characteristic feature of such lesions,
which strengthen the plaques and make it rigid . In our studies, we
have recapitulated the phenomenology of atherosclerotic characteristic
lesions in rabbits with dietary low Mg intake (with increased
cholesterol intake) ([16,65] unpublished findings). Though, the
underlying molecular mechanism behind the initiation of such
inflammatory fatty lesions (with transformed vascular smooth muscle
cells) is still not eloquently understood. Employing transmission
electron microscopy (TEM), in our Mg-deficient rabbit
experimentation suggested to us that, both the vascular smooth muscle
cells and macrophages of the lipid-laden arterial vessels exhibited
necrosis and apoptosis [16,65,66, unpublished findings of Stempak, BT
Altura, M Brust and BM Altura]. Further, investigation using TEM on
cardiac and arterial muscle cells of Mg-deficient rats also showed clear
signs of necrosis as well as apoptosis [66-78; N Shah, BT Altura and
BM Altura, unpublished findings]. Experimentation with high-power
TEM revealed that, these Mg-deficient muscle cells exhibited what is
now termed “necroptosis”.
Necroptosis is a specific type of cell death, which morphologically is
characterized by increases in cell volume and swelling of organelles
(e.g., of mitochondria, Golgi, ER, etc). As a consequence, rupture of
plasma membranes was evident from our studies, which ultimately
results into significant losses of intracellular contents [67-69].
Moreover, similar experimentation in a rodent model system showed
very similar characteristics in arterial and cardiac muscles, under high
power TEM. With the help of progressive research and studies now it is clear that, “necroptosis” occurs in a very controlled and regulated
fashion [67-69] and requires the involvement of two serine/threonine
kinase, receptor-interacting proteins namely, RIPK1 and RIPK3
[67-71]. It has been shown that, release of the cytokine TNF-alpha
(TNF-α) initiates the activation of RIPK1 and RIPK3 [70,71]. Though,
several lines of evidence have been reported that, RIPK1 and RIPK3
can be regulated by the activation and release of other cytokines (e.g.,
IL-1beta, Interferon-gamma) also [68-71].
The RIPK1 and RIPK3 cell-signaling pathway has recently been
shown to be associated in the formation of inflammasomes in many
types of cells and tissues. Our studies have clearly shown that, rat cardiac and vascular smooth muscle cells exposed to short-term Mg
deficiency, exhibit an early and profound elevation in cellular and
plasma lelels of TNF-alpha (i.e., 5-10 fold), IL-beta and interferon-gamma
as well [11,18,42,58-60,72-78]. Interestingly, our
experimentation with necrostatin-1, an inhibitor of RIPK1 and RIPK3
activation, reduces activation and formation of NF-kB in Mg-deficient
peripheral and cerebral vascular smooth muscle cells . Earlier
reports indicate that, NF-kB inhibition is known to reduce necroptosis
and formation of inflammasomes [68-71]. It is notable in this regard
that, Karunkaran et al. state, i.e., “necroptic cell death is activated in
human advanced atherosclerotic plaques” , fits in well with our
findings. Their studies have shown that, macrophages residing within
the plaques were increased in RIPK3 concentration. Hence, there is a
likely possibility that, a major pathway in Mg-deficiency-induced
inflammation and atherogenesis warrants the activation of RIPK1 and
RIPK3. In support of the above contention, our research group has
experimentally shown that there is a 5-8 fold upregulation of RIPK3 in
cardiac and vascular muscle cells obtained from rats exposed to shortterm
Taken together, our on-going findings provide new potential
insights into the underestimated role of Mg deficiency in the USA and
Western World, which results into atherogenesis, inflammations and
presents high risks for coronary artery disease, IHD, and SCD.
For the last 25-30 years, our research group has been investigating
the efficacy of Mg-supplemented or naturally-occurring spring waters
and has suggested their role to prevent the disease risks due to dietaryand/
or metabolically-induced magnesium deficiency
[11,41,42,57-61,65,72-79-83]. Our results, also encourages the idea
that, water intake (e.g., from tap waters, well waters, bottled waters,
beverages using tap/well/spring waters, or desalinated waters) should
contain at least 25-40 mg/liter/day of Mg2+ [58-60,76,77,81]. In this
context, our group has performed several conclusive experiments and
highlighted most of the detrimental pathophysiological implications of
Mg deficiency, which includes decreased cardiac output, decreased
myocardial contractility, decreased coronary blood flows,
mitochondrial release of cytochrome C, lipid peroxidation of cardiac
and vascular muscle membranes, increased cellular levels of NO and
p53, release of cytokines and chemokines, increased cellular entry of
calcium ions and overload, increases in membrane permeability,
myocardial acidification, loss of cellular ATP, DNA damage, shortening
of telomeres, apoptosis, and necroptosis [11,41,42,57-61,72-79-83].
Our results have shown that, the said anomalies can be either
prevented or ameliorated with the administration of adequate Mg2+ mixed with drinking water.
The outcome of our studies could influence the vast long-term
clinical trials in the patients administered with adequate amounts
Mg2+-supplemented waters (i.e., 25-40 mg/liter/day), which could further validate our hypothesis and justify the need for Mg2+-
The authors acknowledge that many of our experiments and human
studies, over five decades, were supported, in part, by Research Grants
from The N.I.H. (to BMA and BTA) and unrestricted grants from
several pharmaceutical companies as well as kind donors.
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