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Int J Clin Exp Med 2013;6(10):861-879
Original Article
Magnesium deficiency upregulates sphingomyelinases in cardiovascular tissues
and cells: cross-talk among proto-oncogenes, Mg2+, NF-κB and ceramide and their
potential relationships to resistant hypertension, atherogenesis and cardiac failure
Burton M Altura, Nilank C Shah, Gatha J Shah, Wenyan Li, Aimin Zhang, Tao Zheng, Zhiqiang Li, Xian-Cheng Jiang, Jose Luis Perez-
Albela, Bella T Altura
Departments of Physiology and Pharmacology, Medicine, The Center for Cardiovascular and Muscle Research, The School of Graduate
Studies Program in Molecular and Cellular Science, State University of New York, Downstate Medical Center, Brooklyn, New York; Bio-
Defense Systems, Inc., Rockville Centre, New York; Department of Anatomy and Cell Biology, State University of New York, Downstate
Medical Center, Brooklyn, New York; Instituto Bien de Salud, Lima, Peru
Received October 1, 2013; Accepted October 27, 2013; Epub October 25, 2013; Published October 30, 2013
Abstract: The present study tested the hypotheses that 1) short-term (ST) dietary deficiency of magnesium (MgD; 21 days) in rats
would result in the upregulation of neutral-, acid-, and alkaline- sphingomyelinases SMases) in cardiac and vascular smooth muscles
(VSMCs), 2) ST MgD would result in an upregulation of proto-oncogenes, i.e., c-Fos and c-Jun, as well as the p65 and c-Rel
components of NF-κB in cardiac and VSMCs, 3) low levels of Mg2+ added to drinking water would either prevent or greatly reduce the
upregulation of the SMases and proto-oncogene expression, 4) exposure of primary cultured VSMCs to low extracellular Mg2+
concentration would lead to release of ceramide in both cerebral and aortic VSMCs, 5) specific inhibitors of neutral- and acid-SMAs
would reduce the release of ceramide in cultured VSMCs exposed to low extracellular Mg2+, and 6) specific inhibitors of neutral- and
acid-SMases would lead to reductions in the expression of c-fos, c-Jun, and NF-κB components. The data indicate that neutral-, acid-
and alkaline-SMases exist in rat cardiac and VSMCs. ST MgD resulted in over 150% increases in SMase activity and proto-oncogene
expression in left and right ventricular muscle, atrial muscle, and abdominal aortic smooth muscle; even very low levels of Mg2+ added
to drinking water either prevented or ameliorated the activation of all 3-SMases as well as expression of c-Fos and c-Jun; scyphostatin
and desipramine reduced the low Mg2+ - induced expression of the proto-oncogenes as well as p65 and c-Rel in VSMCs. Exposure of
the VSMCs to low Mg2+ resulted in more than a 100% increase in release of ceramide; scyphostatin and desipramine reduced greatly
the release of ceramide from the VSMCs. We believe when the present data are viewed in light of our previous, recent findings on the
effects of Mg deficiency on most of the major enzymes in the sphingomyelin-ceramide pathway, that they could provide a rational basis
for the treatment and prevention of drug-resistant hypertension, atherogenesis, and difficult-to-treat forms of cardiac failure.
(IJCEM1310002).
Keywords: Neutral-sphingomyelinase, acid-sphingomyelinase, alkaline-sphingomyelinase, water-borne magnesium, cardiac muscle,
vascular muscle
Address correspondence to: Dr. Burton M Altura, Departments of Physiology and Pharmacology, Medicine, The Center for
Cardiovascular and Muscle Research, The School of Graduate Studies Program in Molecular and Cellular Science, State University of
New York, Downstate Medical Center, Box 31, 50 Clarkson Avenue, Brooklyn, NY 11203-2098. Tel: 718-270-2194; Fax: 718-270-3103;
E-mail: baltura@downstate.edu
Original Article
Magnesium deficiency upregulates sphingomyelinases in cardiovascular tissues
and cells: cross-talk among proto-oncogenes, Mg2+, NF-κB and ceramide and their
potential relationships to resistant hypertension, atherogenesis and cardiac failure
Burton M Altura, Nilank C Shah, Gatha J Shah, Wenyan Li, Aimin Zhang, Tao Zheng, Zhiqiang Li, Xian-Cheng Jiang, Jose Luis Perez-
Albela, Bella T Altura
Departments of Physiology and Pharmacology, Medicine, The Center for Cardiovascular and Muscle Research, The School of Graduate
Studies Program in Molecular and Cellular Science, State University of New York, Downstate Medical Center, Brooklyn, New York; Bio-
Defense Systems, Inc., Rockville Centre, New York; Department of Anatomy and Cell Biology, State University of New York, Downstate
Medical Center, Brooklyn, New York; Instituto Bien de Salud, Lima, Peru
Received October 1, 2013; Accepted October 27, 2013; Epub October 25, 2013; Published October 30, 2013
Abstract: The present study tested the hypotheses that 1) short-term (ST) dietary deficiency of magnesium (MgD; 21 days) in rats
would result in the upregulation of neutral-, acid-, and alkaline- sphingomyelinases SMases) in cardiac and vascular smooth muscles
(VSMCs), 2) ST MgD would result in an upregulation of proto-oncogenes, i.e., c-Fos and c-Jun, as well as the p65 and c-Rel
components of NF-κB in cardiac and VSMCs, 3) low levels of Mg2+ added to drinking water would either prevent or greatly reduce the
upregulation of the SMases and proto-oncogene expression, 4) exposure of primary cultured VSMCs to low extracellular Mg2+
concentration would lead to release of ceramide in both cerebral and aortic VSMCs, 5) specific inhibitors of neutral- and acid-SMAs
would reduce the release of ceramide in cultured VSMCs exposed to low extracellular Mg2+, and 6) specific inhibitors of neutral- and
acid-SMases would lead to reductions in the expression of c-fos, c-Jun, and NF-κB components. The data indicate that neutral-, acid-
and alkaline-SMases exist in rat cardiac and VSMCs. ST MgD resulted in over 150% increases in SMase activity and proto-oncogene
expression in left and right ventricular muscle, atrial muscle, and abdominal aortic smooth muscle; even very low levels of Mg2+ added
to drinking water either prevented or ameliorated the activation of all 3-SMases as well as expression of c-Fos and c-Jun; scyphostatin
and desipramine reduced the low Mg2+ - induced expression of the proto-oncogenes as well as p65 and c-Rel in VSMCs. Exposure of
the VSMCs to low Mg2+ resulted in more than a 100% increase in release of ceramide; scyphostatin and desipramine reduced greatly
the release of ceramide from the VSMCs. We believe when the present data are viewed in light of our previous, recent findings on the
effects of Mg deficiency on most of the major enzymes in the sphingomyelin-ceramide pathway, that they could provide a rational basis
for the treatment and prevention of drug-resistant hypertension, atherogenesis, and difficult-to-treat forms of cardiac failure.
(IJCEM1310002).
Keywords: Neutral-sphingomyelinase, acid-sphingomyelinase, alkaline-sphingomyelinase, water-borne magnesium, cardiac muscle,
vascular muscle
Address correspondence to: Dr. Burton M Altura, Departments of Physiology and Pharmacology, Medicine, The Center for
Cardiovascular and Muscle Research, The School of Graduate Studies Program in Molecular and Cellular Science, State University of
New York, Downstate Medical Center, Box 31, 50 Clarkson Avenue, Brooklyn, NY 11203-2098. Tel: 718-270-2194; Fax: 718-270-3103;
E-mail: baltura@downstate.edu
