Cardiovascular Therapeutics - Applications of Biotechnology in Cardiovascular Therapeutics - page 11

ability to understand mitochondrial dysfunction has been hindered by an absence
of molecular biomarkers defining the various degrees of injury. As an attempt to
characterize the impact of ischemic damage on mitochondrial proteome biology,
an in vitro model of cardiac mitochondria injury in mice was established to
examine two stress conditions: reversible injury induced by mild calcium over-
load and irreversible injury induced by hypotonic stimuli (Zhang et al. 2008 ).
Both forms of injury had a drastic impact on the proteome biology of cardiac
mitochondria. Altered mitochondrial function was concomitant with significant
protein loss/shedding from the injured organelles. In the setting of mild calcium
overload, mitochondria retained functionality despite the release of numerous
proteins, and the majority of mitochondria remained intact. In contrast, hypo-
tonic stimuli caused severe damage to mitochondrial structure and function,
induced increased oxidative modification of mitochondrial proteins, and brought
about detrimental changes to the subproteomes of the inner mitochondrial mem-
brane and matrix. Key observations made by the in vitro model were validated
by using an established in vivo murine model of regional myocardial ischemic
injury. This preclinical investigation provides function and suborganelle location
information on a repertoire of cardiac mitochondrial proteins sensitive to isch-
emia reperfusion stress, and highlights protein clusters potentially involved in
mitochondrial dysfunction in the setting of ischemic injury.

Cardiac Protein Databases

HEART 2D PAGE database of human cardiac proteins have been established at the
German Heart Institute, Berlin: http://userpage.chemie.fu-berlin.de/~pleiss/dhzb.
html (accessed 3 Jan 2011). It contains data on proteins identified on the 2D PAGE
maps of ventricle and atrium of human heart. It contains protein expression charac-
teristics for patients suffering from dilated cardiomyopathy (DCM).

Proteomics of Dilated Cardiomyopathy and Heart Failure

Mutations in sarcomere protein genes account for approximately 10% of cases of
familial DCM. Several studies have shown that expression of about 100 cardiac
proteins is significantly different from normal in DCM and most of these proteins
are less abundant in the diseased than in the normal heart. Impairment of expression
of several cardiac proteins in DCM can be demonstrated by 2DGE. Many of these
proteins have been identified by chemical methods and are classified into three
functional classes:

• Cytoskeletal and myofibrillar proteins

• Proteins associated with mitochondria and energy production

• Proteins associated with stress response such as heat shock protein 27

Correlation of the changes in proteins to altered cellular function is a challenge.
Studies on samples from human diseased tissues are difficult to interpret because
of large number of variables. An alternative approach is animal models of human