Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 693

Current vectors are genetically modified, safe viruses (e.g., adenoviruses,
lentiviruses, retroviruses, and adeno-associated virus) 13 that unload the therapeutic
human gene into target cells. Gene therapy vectors using adeno-associated virus
can lodge without incorporating the genome (extrachromosomal residence) of host
cells. In particular, recombinant human adenoviruses and adeno-associated virus
efficiently deliver and express their genomes in both dividing and quiescent cells.
Adeno-associated virus can cause a long-lasting gene expression with respect to
adenovirus, because of its minimal immunogenicity. Major drawbacks comprise
oncogenic transformation and inflammation with elimination of infected cells.
Non-viral gene transfer uses plasmids, polymers, and liposomes, 14 which are
less expensive and safer than viral vectors, but less efficient. Manufactured non-
viral vectors with low toxicity and immunogenicity can efficiently enter into cells,
but yield low gene expression.
Genetic transfer to restore a normal cardiac function struggles against car-
diomyocyte apoptosis and targets angiogenesis using growth factors and cytokines
(VEGFa 121 ,VEGFa 165 , VEGFc, FGF4, IGF1, CSF3, and erythropoietin), 15 nervous
control 16 (e.g., C-terminus of -adrenergic receptors and adenylate cyclase AC6), 17

and Ca 2 + handling during excitation-contraction coupling (systole) and relaxation

β

13 Adeno-associated virus is a non-enveloped species of the Dependovirus genus (synonym: adeno-
associated virus set) of the Parvoviridae family that contains a single-stranded DNA in an
icosahedral capsid (proteic shell). This small virus infects humans without causing disease, but
only a very mild immune response.
14 Liposome is an artificial lipid capsule with an aqueous core with therapeutic DNA that is able to
cross the plasma membrane.
15 Receptor CSF3R resides on cardiomyocytes and endothelial cells. Factor CSF3 represses
apoptosis, increases NO production, and supports angiogenesis, as it enhances proliferation and
migration of endothelial cells. Both CSF3 and erythropoietin mobilize hematopoietic cells and
endothelial progenitors from the bone marrow. They activate JaK2 and its anti-apoptotic and
angiogenic signaling via STAT3, STAT5, the PI3K-PKB axis, and MAPK module. In addition,
CSF3 promotes early myocardial healing via TGF β 1 and prevents later excessive fibrosis, as it
hampers angiotensin-2 receptor AT 1 and TNF

α

. The Epo receptor is also synthesized in both
ventriculomyocytes and endothelial cells. Erythropoietin, which is liberated by cardiomyocytes,
causes secretion of sonic Hedgehog from cardiomyocytes; it can then launches angiogenesis
by stimulating cardiomyocytes to release VEGF and angiopoietin-1. Erythropoietin prevents
apoptosis of endothelial cells and cardiomyocytes, as it activates PKC and PI3K-PKB pathway.
In addition, Epo fosters cardiac mitochondrion genesis.
16 In the heart,

1-adrenergic receptors are the predominant subtype.
17 Cardiac failure is characterized by a reduction of plasmalemmal density of β 1-adrenoceptors
and by an uncoupling of these receptors from G proteins (desensitization). The C-terminus of β -
adrenergic receptor, a GRK2 inhibitor, impedes recruitment of G-protein-coupled receptor kinase
GRK2, which phosphorylates (desensitizes) β -adrenoceptors and promotes binding to β -arrestins,
thereby supporting cAMP signaling. Adenylate cyclase-6 increases Ca 2 + handling via PKA, PI3K-
PKB, and ATF3 pathways.

β