Sandbox

Coronary Heart Disease

Cardio Protective Effect

The mature spherical HDL particle is composed of enzymes, such as paraoxonase, platelet-activating factor acetylhydrolase (PAF-AH or Lp-PLA2), lecithin-cholesterol acyl transferase (LCAT), apolipoproteins (apoA-I and apoA-II), lipid molecules, such as triglyceride, cholesterol, phospholipids and bioactive lipid molecules, including sphingosine 1-phosphate (S1P) and related lysosphingolipids. The antiatherogenic actions of HDL-C are complex and are mediated through the some of the aforementioned components. HDL-C plays a major role in reverse cholesterol transport, mobilizing cholesterol from the periphery to the liver. In addition, cardioprotective effects of HDL-C include endothelial protection, anti-inflammatory activity, as well as antioxidant and antithrombotic effects and maintenance of low blood viscosity through a permissive action on red cell deformability.

• Apo A-I :
  • Several studies have shown that high-density lipoprotein (HDL)-cholesterol is antiatherogenic and serves a role in mediating cholesterol efflux from cells. Macrophage cholesterol efflux is a process whereby excess cholesterol in cells and in atherosclerotic plaques is removed. Current data indicate that the plasma HDL associated apolipoprotein M (apoM) levels modulate the ability of plasma to mobilize cellular cholesterol and protects against experimental atherosclerosis.
  • Animal models have shown that the somatic gene transfer of human apo A-I can prevent the development of atherosclerosis or reverse preexisting atherosclerosis or its role in the anti-endotoxin function of HDL.
  • Current data suggest that, ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in endothelial cells, and the scavenger receptor B type 1 mediate multiple intracellular signaling pathways as well as the efflux of cholesterol and/or oxysterols in response to apoA-I/HDL.

• ApoA-I/SR-BI :
  • HDL also protects endothelial cells from apoptosis and promotes their growth and their migration via SR-BI-initiated signaling. Recent studies have shown that SR-BI is also expressed in endothelial cells (ECs) and mediates HDL-associated apoA-I-induced stimulation of endothelial nitric oxide synthase (eNOS), inhibition of monocyte adhesion to endothelial cells, vasorelaxation, and re-endothelialization following perivascular electric injury.
  • It is also proposed that the anti-apoptotic and proliferative effects of apoA-I are mediated through F1-ATPase-catalysed ADP production and subsequent P2Y13 receptor stimulation, thus contributing to the atheroprotective functions.
  • HDL promotes the production of signaling molecule nitric oxide (NO) by upregulating endothelial NO synthase (eNOS) expression, by maintaining the lipid environment in caveolae where eNOS is colocalized with partner signaling molecules, and by stimulating eNOS as a result of kinase cascade activation by the high-affinity HDL receptor scavenger receptor class B type I (SR-BI). Studies have shown the ability of recombiant HDL (rHDL) or reconstituted apoA-I with phospholipids but without cholesterol to stimulate eNOS activation and to repair damaged endothelium and to enhance ischemia-induced angiogenesis through stimulation of endothelial progenitor cells (EPCs) in vivo. The enhancement of SR-BI expression by simvastatin results in enhancement of HDL- and rHDL-induced eNOS activation and subsequent inhibition of adhesion molecule expression, which supports the role of SR-BI in HDL-induced anti-inflammatory actions.

• Sphingosine 1-phosphate (S1P) :
  • Fractionation by density gradient centrifugation has shown that sphingosine 1-phosphate (S1P) is concentrated in the lipoprotein fraction with a rank order of HDL > LDL > VLDL, and to a lesser extent, in the lipoprotein-deficient albumin fraction when expressed as pmol/mg protein. Thus, HDL-S1P has been proposed to mediate a variety of HDL-induced actions.
  • S1P has been shown to improve ischemia/reperfusion-induced injury in vivo and in vitro with inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area.
  • The pro-atherogenic adhesion molecule expression elicited by S1P disappears in the presence of physiological concentrations of HDL in a manner sensitive to SR-BI.

• Paraoxonase 1 (PON1) :
  • Paraoxonase is an esterase enzyme that is synthesized by the liver and it is associated with HDL in the blood. There is considerable evidence to prove the fact that the antioxidant activity of HDL is largely due to the PON1 which is located on it. A atorvastatin study demonstrating HDL-related antioxidant activity as well as lipid-lowering properties proves PON1 action of prevents LDL oxidation and inactivates LDL-derived oxidized phospholipids.
  • Studies have suggested that serum antioxidant activity of PON1 was an important factor which provided protection from oxidative stress and lipid peroxidation in CAD. Thus, evaluating the effects of PON 1 for CAD patients may be promising in the treatment and prognosis of CAD.
  • Studies have shown pomegranate to be a potent anti-atherogenic agent because of its antioxidants which have the ability to increase the activity of the HDL-associated paraoxonase 1 (PON1), which breaks down harmful oxidized lipids in lipoproteins, in macrophages, and in atherosclerotic plaques.

• Indirect cardioprotective actions :
  • It includes, HDL capacities to promote pancreatic β-cell insulin secretion, to protect pancreatic β cells from apoptosis, and to enhance glucose uptake by skeletal muscle myocytes. Studies have shown that inhibition of insulin-stimulated glucose uptake in primary human skeletal myotubes by conditioned media from macrophages pre-incubated with LDL was restored by co-treatment with HDL.
  • In vascular smooth muscles, HDL tempers proinflammatory, promigratory, and degradative processes, and through actions on endothelium and platelets HDL is antithrombotic. The antithrombotic properties may also be related to the abilities of HDL to attenuate the expression of tissue factor and selectins, to downregulate thrombin generation via the protein C pathway, and to directly and indirectly blunt platelet activation. Thus, in addition to its cholesterol-transporting properties, HDL favorably regulates endothelial cell phenotype and reduces the risk of thrombosis.
  • Furthermore, HDL decreases white adipose tissue mass, increases energy expenditure, and promotes the production of adipose-derived cytokine adiponectin that has its own vascular-protective properties.