Hyperhomocysteinemia: a missing link to dysfunctional HDL via paraoxanase-1

Area of Science:

• Cardiovascular Biology
• Biochemistry
• Molecular Medicine

Background:

• Paraoxonase-1 (PON1) is an enzyme associated with high-density lipoprotein (HDL), crucial for its antioxidant and antiatherosclerotic functions.
• PON1 deficiency leads to dysfunctional HDL, a state implicated in cardiovascular disorders.
• Hyperhomocysteinemia (HHcy) is a known risk factor for cardiovascular disease, associated with vascular dysfunction and extracellular matrix (ECM) remodeling, but its precise mechanism remains unclear.

Purpose of the Study:

• To investigate the hypothesis that dysfunctional HDL, caused by PON1 deficiency, contributes to endothelial impairment and atherogenesis through HHcy-induced ECM remodeling.
• To elucidate the molecular mechanisms linking PON1 deficiency, HHcy, and vascular pathology.

Main Methods:

• Utilized C57BL6/J and PON1 knockout (KO) mice fed an atherogenic diet.
• Assessed cardiac function and plasma homocysteine (Hcy) levels.
• Measured the expression of key proteins involved in vascular function and inflammation, including Akt, Asymmetric Dimethylarginine (ADMA), Dimethylarginine Dimethylaminohydrolase (DDAH), endothelial nitric oxide synthase (eNOS), connexins (Cx-37, Cx-40), and matrix metalloproteinase-9 (MMP-9).

Main Results:

• PON1 KO mice on an atherogenic diet exhibited decreased cardiac function and elevated plasma Hcy levels compared to controls.
• Expression of Akt, eNOS, DDAH, Cx-37, and Cx-40 was reduced in PON1 KO mice.
• Expression of MMP-9 and ADMA was increased in PON1 KO mice, indicating vascular inflammation and dysfunction.

Conclusions:

• HHcy plays a significant role in HDL dysfunction associated with PON1 deficiency.
• PON1 deficiency contributes to vascular endothelial impairment and atherosclerosis.
• MMP-9-induced vascular remodeling is a key mechanism through which HHcy, in the context of PON1 deficiency, promotes atherogenesis.