Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 202

membrane phospholipids such as cardiolipin at the inner mitochondrial membrane
that then prevents respiratory chain activity. The combined effects of ROS and
augmented Ca 2 + concentration in the mitochondrial matrix causes opening of the
non-specific mitochondrial permeability transition pore, hence free passage of small
cytosolic molecules (

1.5 kDa). Therefore, pore opening increases the mitochon-
drial matrix volume, disrupts mitochondrial outer membrane, and provokes cell
death (Vol. 2 - Chap. 4. Cell Survival and Death).
Ischemic postconditioning that consists of alternating, brief periods of ischemia
and reperfusion is effective when applied at the onset of reperfusion. It includes
formation and release of autacoids and cytokines, maintenance of acidosis during
early reperfusion, activation of protein kinases, and repression of opening of
mitochondrial permeability transition pore.
During hypoxia, as HIF

<

is not targeted by the oxygen sensor prolyl hydroxylase
that enables it interact with von Hippel-Lindau ubiquitin ligase for proteasome
degradation, this subunit accumulates and forms HIF

α

heterodimer. 20 Following
the recruitment of CBP and P300 coactivators, HIF causes target gene transcription.
Hypoxia-inducible factor provokes [ 353 ]: (1) expression of glucose transporters
GLUT1 and GLUT4; (2) that of glycolytic enzymes to balance decayed cell
respiration; (3) that of lactate dehydrogenase-A that converts pyruvate into lac-
tate, hence diverting pyruvate away from the mitochondria; (4) that of pyruvate
dehydrogenase kinase that impedes conversion of pyruvate into acetyl coenzyme-
A, which enter the Krebs cycle; (5) switch form COx4-1 to COx4-2 subunit in
complex IVto optimize the efficiency of electron transport; and (6) mitochondrial
autophagy. In addition, to prevent mitochondrial permeability transition pore open-
ing, HIF1

αβ

elicits [ 353 ]: (1) adenosine production to stimulate the PI3K-PKB
pathway; (2) NO generation by NOS2 to activate protein kinase-G for opening
of mitochondrial K AT P channels that promotes production of low levels of ROS
messengers; as well as (3) activation of inner mitochondrial membrane uncoupling
proteins UCP2 and UCP3 to limit mitochondrial generation of ROS concentrations.
Produced ROS messengers oxidize (inactivate) PTen, thus activating survival PKB
kinase.

α

5.2.4 Nuclear GPCRs

G-protein-coupled receptors, such as -adrenergic, angiotensin-2 AT 1 and

AT 2 , apelin, bradykinin B 2 , endothelin, metabotropic glutamate, lysophosphatidic
acid, platelet-activating factor, and prostaglandin receptors target the nuclear mem-
brane [ 354 ].
Furthermore, numerous GPCRs contain nuclear localization sequences that
enable them to cross nuclear pore complexes, hence to move from the outer to
the inner nuclear membrane, thereby delivering signals toward the cytoplasm or
the nucleoplasm.

α 1- and β

20 Three HIF-

α isoforms (HIF α 1-HIF α 3) are encoded by distinct genes.