High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin

Abstract

Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles “Del” and “4G”. The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations (Del/4G) are at high risk for the onset of CVDs.

Essential role of ATP6AP2 enrichment in caveolae/lipid raft microdomains for the induction of neuronal differentiation of stem cells

“…The role of ATP6AP2-over/underexpressed ADSCs should also be clarified during differentiation into other lineages of cells (hepatocytes, nephron progenitor cells, cardiomyocytes, etc.) in a perspective of cell therapy; for example, cardiovascular diseases where hypertension and hypercholesterolemia were correlated with the RAS components [ 59 , 25 ], which in turn were associated with ATP6AP2.…”

“…Fresh peripheral blood (20 ml) was collected from healthy and ND subjects. Peripheral blood mononuclear cells (PBMCs) were separated and cultured according to AlBacha et al [ 25 ]. No significant variations on the number of isolated cells were obtained between healthy and ND subjects (data not shown).…”

Pharmacogenetics of statin therapy and the endothelial function parameters in patients with type 2 diabetes mellitus

“…Связь этого полиморфного маркера с развитием атеросклероза имеет четкие патогенетические механизмы, т.к. повышение уровня ACE (при генотипе DD) приводит к гиперпродукции ангиотензина II -мощного вазоактивного и ростстимулирующего фак-тора, являющегося медиатором прогрессирования ССП при СД2 [14]. По данным наших предыдущих работ [7], показана ассоциация маркера I/D гена ACE с развитием диабетической нефропатии при СД1, но не с риском хронической болезни почек при СД2.…”

Is plasminogen activator inhibitor‐1 a physiological bottleneck bridging major depressive disorder and cardiovascular disease?

“…Likewise, 4G SERPINE1 is associated with an increased rate of occurrence of hypertension–hypercholesterolaemia (AlBacha et al . ) as well as increased mortality in patients experiencing septic shock (Lorente et al . ).…”

“…More recent evidence suggests that the 4G/5G polymorphism is a significant factor in persistence of thrombosis in patients experiencing post-thrombotic syndrome, even in the presence of anticoagulant therapies (Incalcaterra et al 2014). Likewise, 4G SERPINE1 is associated with an increased rate of occurrence of hypertension-hypercholesterolaemia (AlBacha et al 2015) as well as increased mortality in patients experiencing septic shock (Lorente et al 2015).…”