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Increased Levels of Human Carotid Lesion Linoleic Acid Hydroperoxide in Symptomatic and Asymptomatic Patients Is Inversely Correlated with Serum HDL and Paraoxonase 1 Activity.

Cohen E, Aviram M, Khatib S, Rabin A, Mannheim D, Karmeli R, Vaya J - J Lipids (2012)

Bottom Line: The PON1-specific inhibitor 2-hydroxyquinoline almost completely inhibited paraoxonase and lactonase activities, while only moderately inhibiting arylesterase activity.Oxysterol and triglyceride levels in plaques from symptomatic and asymptomatic patients did not differ significantly, but plaques from symptomatic patients had significantly higher (135%) linoleic acid hydroperoxide (LA-13OOH) levels.Their serum PON1 activity, cholesterol and triglyceride levels did not differ significantly, but symptomatic patients had significantly lower (28%) serum HDL levels and higher (18%) HbA1c levels.

View Article: PubMed Central - PubMed

Affiliation: Oxidative Stress Research Laboratory, Migal-Galilee Technology Center and Tel Hai College, P.O. Box 831, Kiryat Shmona 11016, Israel.

ABSTRACT
Human carotid plaque components interact directly with circulating blood elements and thus they might affect each other. We determined plaque paraoxonase1 (PON1) hydrolytic-catalytic activity and compared plaque and blood levels of lipids, HDL, PON1, and HbA1c, as well as plaque-oxidized lipids in symptomatic and asymptomatic patients. Human carotid plaques were obtained from symptomatic and asymptomatic patients undergoing routine endarterectomy, and the lesions were ground and extracted for PON activity and lipid content determinations. Plaque PONs preserved paraoxonase, arylesterase, and lactonase activities. The PON1-specific inhibitor 2-hydroxyquinoline almost completely inhibited paraoxonase and lactonase activities, while only moderately inhibiting arylesterase activity. Oxysterol and triglyceride levels in plaques from symptomatic and asymptomatic patients did not differ significantly, but plaques from symptomatic patients had significantly higher (135%) linoleic acid hydroperoxide (LA-13OOH) levels. Their serum PON1 activity, cholesterol and triglyceride levels did not differ significantly, but symptomatic patients had significantly lower (28%) serum HDL levels and higher (18%) HbA1c levels. Thus LA-13OOH, a major atherogenic plaque element, showed significant negative correlations with serum PON1 activity and HDL levels, and a positive correlation with the prodiabetic atherogenic HbA1c. Plaque PON1 retains its activity and may decrease plaque atherogenicity by reducing specific oxidized lipids (e.g., LA-13OOH). The inverse correlation between plaque LA-13OOH level and serum HDL level and PON1 activity suggests a role for serum HDL and PON1 in LA-13OOH accumulation.

No MeSH data available.


Related in: MedlinePlus

Serum PON1 activity versus serum HDL cholesterol. Serum PON1 activity is not correlated with serum HDL cholesterol levels.
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fig3: Serum PON1 activity versus serum HDL cholesterol. Serum PON1 activity is not correlated with serum HDL cholesterol levels.

Mentions: A distinction between symptomatic and asymptomatic patients through the identification of biomarkers could provide information on symptom occurrence. Such biomarkers are not yet available but are needed to make appropriate decisions on the type of intervention required [8]. Previous studies from our group have shown that LA-13OOH is present in the lipid extract of the human carotid plaque, and that it specifically inhibits rePON1 activity in a dose- and time-dependent manner. During PON1's interaction with lesion LA-13OOH, the enzyme displayed a peroxidase-type of catalysis, reducing LA-13OOH to LA-OH (hydroxide) via the PON1 amino acid Cys284 [22]. Thus, the levels of LA-13OOH in symptomatic and asymptomatic patients were compared and correlated with antiatherogenic compounds in the plaque, or in the serum derived from these patients. Symptomatic patients had significantly higher levels of LA-13OOH in their plaques than their asymptomatic counterparts. In addition, LA-13OOH levels in the plaque were significantly inversely correlated with serum PON1 activity (Figure 2(a)) and with serum HDL cholesterol (Figure 2(b)). Although PON1 is an HDL-associated enzyme, HDL particles are highly heterogeneous in their structure, intravascular metabolism, and biological activities [33]. Furthermore, PON1 is only present on a relatively small fraction of the HDL particles, mostly on the HDL3 subfraction. Thus, the amount of the HDL in the blood is not necessarily correlated with serum PON1 activity. Indeed, in this study, serum PON1 lactonase activity was not correlated with serum HDL levels (Figure 3). These results indicate that LA-13OOH might be affected, independently, by both serum PON1 and serum HDL level. As plaque LA-13OOH has been shown to interact with and inhibit rePON1 [22], and since PON1 is present and active, in both blood and the atherosclerotic plaque, we determined PON1 activity in serum and plaques derived from the same individuals and compared them in symptomatic versus asymptomatic patients. Our results showed no differences in plaque PON activity between symptomatic and asymptomatic atherosclerotic patients (P = 0.8). Serum PON1 activity in the symptomatic patients was lower than in the asymptomatic patients, although this difference was not significant (P = 0.14) (Table 2). Plaque PON activity may be attributed to both PON1 and the intracellular enzyme PON2, which may not be affected by the presence of LA-13OOH. In addition, it has been previously shown that inhibition of rePON1 by LA-13OOH can be prevented if certain thiols, such as the amino acid cysteine, are present, and that PON1 inhibition by LA-13OOH can be partially recovered if a thiol is added to the incubation system. LA-13OOH probably oxidizes the PON1 Cys284 to sulfenic acid, which can then be further oxidized to sulfinic and sulfonic acid derivatives. In the presence of thiol, the sulfenic acid derivative of Cys284 can be reduced back to thiol; however, if the oxidation proceeds further, addition of an external thiol can no longer reverse the reaction [22]. We can, therefore, hypothesize that the presence of free cysteine in the blood and in the plaque may also prevent LA-13OOH-induced PON1 inactivation.


Increased Levels of Human Carotid Lesion Linoleic Acid Hydroperoxide in Symptomatic and Asymptomatic Patients Is Inversely Correlated with Serum HDL and Paraoxonase 1 Activity.

Cohen E, Aviram M, Khatib S, Rabin A, Mannheim D, Karmeli R, Vaya J - J Lipids (2012)

Serum PON1 activity versus serum HDL cholesterol. Serum PON1 activity is not correlated with serum HDL cholesterol levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368548&req=5

fig3: Serum PON1 activity versus serum HDL cholesterol. Serum PON1 activity is not correlated with serum HDL cholesterol levels.
Mentions: A distinction between symptomatic and asymptomatic patients through the identification of biomarkers could provide information on symptom occurrence. Such biomarkers are not yet available but are needed to make appropriate decisions on the type of intervention required [8]. Previous studies from our group have shown that LA-13OOH is present in the lipid extract of the human carotid plaque, and that it specifically inhibits rePON1 activity in a dose- and time-dependent manner. During PON1's interaction with lesion LA-13OOH, the enzyme displayed a peroxidase-type of catalysis, reducing LA-13OOH to LA-OH (hydroxide) via the PON1 amino acid Cys284 [22]. Thus, the levels of LA-13OOH in symptomatic and asymptomatic patients were compared and correlated with antiatherogenic compounds in the plaque, or in the serum derived from these patients. Symptomatic patients had significantly higher levels of LA-13OOH in their plaques than their asymptomatic counterparts. In addition, LA-13OOH levels in the plaque were significantly inversely correlated with serum PON1 activity (Figure 2(a)) and with serum HDL cholesterol (Figure 2(b)). Although PON1 is an HDL-associated enzyme, HDL particles are highly heterogeneous in their structure, intravascular metabolism, and biological activities [33]. Furthermore, PON1 is only present on a relatively small fraction of the HDL particles, mostly on the HDL3 subfraction. Thus, the amount of the HDL in the blood is not necessarily correlated with serum PON1 activity. Indeed, in this study, serum PON1 lactonase activity was not correlated with serum HDL levels (Figure 3). These results indicate that LA-13OOH might be affected, independently, by both serum PON1 and serum HDL level. As plaque LA-13OOH has been shown to interact with and inhibit rePON1 [22], and since PON1 is present and active, in both blood and the atherosclerotic plaque, we determined PON1 activity in serum and plaques derived from the same individuals and compared them in symptomatic versus asymptomatic patients. Our results showed no differences in plaque PON activity between symptomatic and asymptomatic atherosclerotic patients (P = 0.8). Serum PON1 activity in the symptomatic patients was lower than in the asymptomatic patients, although this difference was not significant (P = 0.14) (Table 2). Plaque PON activity may be attributed to both PON1 and the intracellular enzyme PON2, which may not be affected by the presence of LA-13OOH. In addition, it has been previously shown that inhibition of rePON1 by LA-13OOH can be prevented if certain thiols, such as the amino acid cysteine, are present, and that PON1 inhibition by LA-13OOH can be partially recovered if a thiol is added to the incubation system. LA-13OOH probably oxidizes the PON1 Cys284 to sulfenic acid, which can then be further oxidized to sulfinic and sulfonic acid derivatives. In the presence of thiol, the sulfenic acid derivative of Cys284 can be reduced back to thiol; however, if the oxidation proceeds further, addition of an external thiol can no longer reverse the reaction [22]. We can, therefore, hypothesize that the presence of free cysteine in the blood and in the plaque may also prevent LA-13OOH-induced PON1 inactivation.

Bottom Line: The PON1-specific inhibitor 2-hydroxyquinoline almost completely inhibited paraoxonase and lactonase activities, while only moderately inhibiting arylesterase activity.Oxysterol and triglyceride levels in plaques from symptomatic and asymptomatic patients did not differ significantly, but plaques from symptomatic patients had significantly higher (135%) linoleic acid hydroperoxide (LA-13OOH) levels.Their serum PON1 activity, cholesterol and triglyceride levels did not differ significantly, but symptomatic patients had significantly lower (28%) serum HDL levels and higher (18%) HbA1c levels.

View Article: PubMed Central - PubMed

Affiliation: Oxidative Stress Research Laboratory, Migal-Galilee Technology Center and Tel Hai College, P.O. Box 831, Kiryat Shmona 11016, Israel.

ABSTRACT
Human carotid plaque components interact directly with circulating blood elements and thus they might affect each other. We determined plaque paraoxonase1 (PON1) hydrolytic-catalytic activity and compared plaque and blood levels of lipids, HDL, PON1, and HbA1c, as well as plaque-oxidized lipids in symptomatic and asymptomatic patients. Human carotid plaques were obtained from symptomatic and asymptomatic patients undergoing routine endarterectomy, and the lesions were ground and extracted for PON activity and lipid content determinations. Plaque PONs preserved paraoxonase, arylesterase, and lactonase activities. The PON1-specific inhibitor 2-hydroxyquinoline almost completely inhibited paraoxonase and lactonase activities, while only moderately inhibiting arylesterase activity. Oxysterol and triglyceride levels in plaques from symptomatic and asymptomatic patients did not differ significantly, but plaques from symptomatic patients had significantly higher (135%) linoleic acid hydroperoxide (LA-13OOH) levels. Their serum PON1 activity, cholesterol and triglyceride levels did not differ significantly, but symptomatic patients had significantly lower (28%) serum HDL levels and higher (18%) HbA1c levels. Thus LA-13OOH, a major atherogenic plaque element, showed significant negative correlations with serum PON1 activity and HDL levels, and a positive correlation with the prodiabetic atherogenic HbA1c. Plaque PON1 retains its activity and may decrease plaque atherogenicity by reducing specific oxidized lipids (e.g., LA-13OOH). The inverse correlation between plaque LA-13OOH level and serum HDL level and PON1 activity suggests a role for serum HDL and PON1 in LA-13OOH accumulation.

No MeSH data available.


Related in: MedlinePlus