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Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from
Mabel Toribio1, Kathleen V Fitch1, Lauren Stone1
1Massachusetts General Hospital, Program in Nutritional Metabolism and Harvard Medical School (MT, KVF, LS, MVZ, JL, SKG), Boston, MA, USA.
Insights
Statins significantly altered key proteins in people with HIV (PWH), reducing tissue factor pathway inhibitor (TFPI) and increasing galectin-4 (Gal-4). Pitavastatin showed a greater TFPI reduction than pravastatin, revealing novel mechanisms of statin action.
Area of Science:
- Proteomics and Cardiovascular Disease Research
- HIV/AIDS and Comorbidity Studies
Background:
- People with HIV (PWH) have a higher risk of cardiovascular disease (CVD) due to chronic immune activation, inflammation, and endothelial dysfunction.
- Understanding the molecular mechanisms underlying CVD in PWH is crucial for developing targeted prevention and treatment strategies.
Purpose of the Study:
- To investigate the effects of pitavastatin versus pravastatin on protein biomarkers associated with atherosclerosis and CVD pathways in people with HIV (PWH).
- To identify novel mechanisms through which statins may exert their cardiovascular benefits in the PWH population.
Main Methods:
- A randomized trial (INTREPID) compared pitavastatin (4 mg) to pravastatin (40 mg) in 252 HIV-infected participants with dyslipidemia over 52 weeks.
- A proteomic discovery approach using Proximity Extension Assay technology assessed 92 protein biomarkers in 225 participants' pre- and post-treatment specimens.
- Statistical analyses were performed to determine significant changes in protein levels and their association with lipid parameters and treatment groups.
Main Results:
- Statin treatment significantly decreased levels of tissue factor pathway inhibitor (TFPI), paraoxonase 3 (PON3), and LDL-receptor (LDLR).
- Statin treatment significantly increased levels of galectin-4 (Gal-4) and insulin-like growth factor binding protein 2 (IGFBP-2).
- The reduction in TFPI was significantly greater with pitavastatin compared to pravastatin. Changes in TFPI correlated with changes in LDL-C and Lp-PLA2.
Conclusions:
- Statin therapy in PWH significantly impacts key proteins involved in coagulation, redox signaling, oxidative stress, and glucose metabolism.
- Pitavastatin demonstrated a more pronounced effect on reducing TFPI compared to pravastatin, suggesting potential differential mechanisms of action.
- These findings highlight potential novel pathways through which statins confer cardiovascular benefits in the PWH population.
Background:
People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction.
Methods:
In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4 mg vs. pravastatin 40 mg for 52 weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension Assay technology to determine the effects of statins on key atherosclerosis and CVD pathways among PWH. 225 participants had specimens available for biomarker analysis pre- and post-baseline.
Findings:
The mean age was 49.5 ± 8.0 (mean ± SD), LDL-C 155 ± 25 mg/dl and CD4 count 620 ± 243 cell/mm3. Among all participants, three proteins significantly decreased: tissue factor pathway inhibitor [TFPI; t-statistic = -6.38, FDR p-value<0.0001], paraoxonase 3 [PON3; t-statistic = -4.64, FDR p-value = 0.0003], and LDL-receptor [LDLR; t-statistic = -4.45, FDR p-value = 0.0004]; and two proteins significantly increased galectin-4 [Gal-4; t-statistic = 3.50, FDR p-value = 0.01] and insulin-like growth factor binding protein 2 [IGFBP-2; t-statistic = 3.21, FDR p-value = 0.03]. The change in TFPI was significantly different between the pitavastatin and pravastatin groups. Among all participants, change in TFPI related to the change in LDL-C (r = 0.43, P < 0.0001) and change in Lp-PLA2 (r = 0.29, P < 0.0001).
Interpretation:
Using a proteomics approach, we demonstrated that statins led to a significant reduction in the levels of TFPI, PON3, and LDLR and an increase in Gal-4 and IGFBP-2, key proteins involved in coagulation, redox signaling, oxidative stress, and glucose metabolism. Pitavastatin led to a greater reduction in TFPI than pravastatin. These data highlight potential novel mechanisms of statin effects among PWH. FUND: This work was supported by an investigator-initiated grant to S.K.G. from KOWA Pharmaceuticals America, Inc. and the National Institutes of Health [P30 DK040561; Nutrition Obesity Research Center at Harvard]. M.T. was support by National Institutes of Health [5KL2TR001100-05; Harvard Catalyst KL2 grant].
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