Ph.D Thesis | |
Ph.D Student | Khoury Emad |
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Subject | Hemodynamic and Molecular Mechanisms Underlying the Pathogenesis of Congestive Heart Failure: Role of Corin |
Department | Department of Medicine | Supervisors | PROF. Zaid A. Abassi |
PROF. Doron Aronson |
Background: Heart failure (HF) often leads to
progressive cardiac hypertrophy as well as salt/water retention, and results in
cardiorenal syndrome (CRS). CRS is characterized by renal blunted response to
natriuretic peptides (NPs), i.e., substantially elevated levels of circulating
atrial and b-type NPs (ANP and BNP, respectively) with little or no natriuretic
effect. Corin, a cardiac serine protease, is activated by proprotein convertase
subtilisin/kexin type 6 (PCSK6) and is responsible for converting proANP and
proBNP to biologically active peptides. The involvement of corin and PCSK6 in HF
has not been thoroughly studied or examined simultaneously in the cardiac and
renal tissues in CRS.
Study Aims: To examine the status of the NPs machinery enzymes in
the cardiac and renal tissues of Sprague-Dawley rats with HF.
Methods: HF was induced by the creation of aorto-caval fistula
(ACF) between the abdominal aorta and vena cava. Rats were sacrificed 1, 2, 4,
and 12 weeks following the surgery. Rats with 1-week ACF were divided into 2
subgroups according to renal sodium excretion (compensated and decompensated
ACF). The cardiac and renal expression, abundance, and immunofluorescence of
corin, PCSK6, and furin were studied in the various experimental groups.
Results: Placement of ACF led to CRS manifestations which were in
correlation with HF severity. Cardiac and renal expression of NPs, as well as
their circulating levels were significantly enhanced in all ACF rats.
Interestingly, the abundance of corin and PCSK6 in both the cardiac ventricles
and renal tissues significantly increased in compensated animals of 1-week and
in more advanced stages of the disease, yet decreased in decompensated rats
after 1-week and 12 weeks following ACF placement. In
contrast, furin expression was upregulated in all studied tissues of all ACF
rats. Moreover, cardiac levels of a disintegrin and metalloproteinase
domain-containing protein 10 (ADAM10), and renal
abundance of neprilysin, were increased in all ACF rats, except decompensated
HF. Finally, rats with ACF displayed a unique pattern of corin staining in
cardiac tissue, demonstrating an elevated cytosolic immunoreactive corin
levels. In this context, we report for the first time the existence of an
alternative variant of corin in cardiac and renal tissues of rats, with potentially
a deficient intracellular trafficking to cell surface.
Conclusion: We presume that the
obtained upregulation of cardiac and renal PCSK6/corin in rats with 1-week
compensated HF, as well as at 2 and 4 weeks following ACF placement, may
represent a compensatory mechanism responsible for maintaining normal Na
balance. In contrast, the decline in these two enzymes in both 1-week
decompensated HF and rats with 12 weeks ACF, may
contribute to the pathogenesis of avid sodium retention, cardiac
hypertrophy, and blunted ANP/BNP actions. Moreover, we hypothesize that the
expression of corin alternative exons in HF may lead to the accumulation of
inactive corin in the cellular cytosol, thus contributing to aberrant
production of mature and active NPs.