Cardiovascular Therapeutics - Applications of Biotechnology in Cardiovascular Therapeutics - page 25

preconditioning with low or high nitrate doses. There was significant nitrite-induced
protein modifications (including phosphorylation) revealed by MS-based proteomic
studies. Altered proteins included those involved in metabolism (e.g., aldehyde
dehydrogenase 2), redox regulation (e.g., protein disulfide isomerase A3), contrac-
tile function (e.g., filamin-C), and serine/threonine kinase signaling (e.g., protein
kinase A R1a). Thus, brief elevations in plasma nitrite trigger a concerted cardio-
protective response characterized by persistent changes in cardiac metabolism,
redox stress, and alterations in myocardial signaling. These findings help elucidate
possible mechanisms of nitrite-induced cardioprotection and have implications for
nitrite dosing in therapeutic regimens. A similar mechanism may underpin the
cardioprotective value of physical exercise and a diet containing nitrite/nitrate-
rich foods.
Cardioprotection Based on Study of Cardiac Mitochondrial Proteome
Mitochondria can represent a threat to the cell under hypoxic conditions because
they can generate reactive oxygen species. However, cardiomyocytes are equipped
with an oxygen-sensing pathway that involves prolyl hydroxylase oxygen sensors
and hypoxia-inducible factors, which induces a tightly regulated program to keep
ischemic mitochondrial activity under control (Cadenas et al. 2010 ).
Proteomic methods are useful in studying the cardiac mitochondrial proteome,
which are important, particularly those associated with cell death and protection.
Proteomic data from these studies have contributed to addressing the role of mito-
chondria in cardioprotection (Gucek and Murphy 2010 ).
Protection of the Blood Vessels
Apart from the protection of the myocardium, protection of the coronary arteries as
well as other arteries in the human body is an important consideration in manage-
ment of cardiovascular diseases. Two important processes that require protective
strategies are atherosclerosis of the arterial wall and prevention of proliferation of
endothelium following injury or therapeutic interventions such as angioplasty. The
latter will be discussed in more detail in Chap. 9.
An example of the application of molecular biology to this problem is the study
of Toll-like receptors (TLRs). The capacity of about 10 TLRs to recognize con-
served patterns on many bacterial and viral pathogens is remarkable, but TLRs, in
particular to TLR2 and TLR4, have been assigned detrimental roles in immune and
cardiovascular disease. Using human and murine systems, a study has investigated
the consequence of TLR3 signaling in vascular disease (Cole et al. 2011 ). The
responses of human atheroma-derived smooth muscle cells (AthSMC) and control
aortic smooth muscle cells (AoSMC) were compared to various TLR ligands.
AthSMC exhibited a specific increase in TLR3 expression and TLR3-dependent
functional responses. Exposure to dsRNA in vitro and in vivo induced increased