Ph.D Thesis

Ph.D StudentKhoury Emad
SubjectHemodynamic and Molecular Mechanisms Underlying the
Pathogenesis of Congestive Heart Failure: Role
of Corin
DepartmentDepartment 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.