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Altered cardiac expression of peroxisome proliferator-activated receptor-isoforms in patients with hypertensive heart
María J Goikoetxea1, Javier Beaumont, Arantxa González
1Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
Insights
Cardiac peroxisome proliferator-activated receptor alpha (PPARalpha) expression changes in hypertensive heart disease. An excess inhibitory PPARalpha isoform correlates with heart failure and adverse cardiac remodeling in hypertension.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Hypertension Research
Background:
- Hypertensive heart disease (HHD) involves complex molecular alterations in the myocardium.
- Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a role in cardiac metabolism and inflammation.
- Understanding PPARalpha regulation is crucial for managing HHD progression.
Purpose of the Study:
- To investigate alterations in cardiac PPARalpha expression in patients with HHD.
- To determine the relationship between PPARalpha isoforms and left ventricular hypertrophy (LVH) and heart failure (HF) in hypertension.
Main Methods:
- Endomyocardial biopsies from hypertensive patients without LVH, with LVH, and with LVH and HF were analyzed.
- Western blot and RT-PCR were used to quantify PPARalpha isoforms and target gene expression.
- Histomorphological analysis assessed cardiomyocyte features in LVH and HF groups.
Main Results:
- Native PPARalpha protein expression was reduced in LVH and HF groups compared to controls.
- Truncated, inhibitory PPARalpha protein was significantly overexpressed in the HF group.
- mRNA levels of PPARalpha isoforms were similar across groups, suggesting post-transcriptional regulation.
- Truncated PPARalpha protein correlated with increased cardiomyocyte apoptosis, decreased density, larger left ventricular volumes, and reduced ejection fraction.
Conclusions:
- Post-transcriptional regulation of PPARalpha isoforms is altered in HHD, particularly in patients developing HF.
- Excess truncated PPARalpha may contribute to hypertensive left ventricular dysfunction and adverse cardiac remodeling.
- Targeting PPARalpha isoforms could offer therapeutic strategies for HHD.
Objective:
To investigate whether cardiac expression of the nuclear peroxisome proliferator-activated receptor alpha (PPARalpha) is altered in patients with hypertensive heart disease (HHD).
Methods:
We studied endomyocardial septal biopsies from 24 patients with essential hypertension divided into three groups: 6 without left ventricular hypertrophy (LVH) (HT group), 10 with LVH (LVH group), and 8 with LVH and heart failure (HF) (HF group). The expression of two PPARalpha isoforms (the native active and the truncated inhibitory) was analyzed by Western blot and reverse transcription polymerase chain reaction (RT-PCR), and two PPARalpha target genes were evaluated by RT-PCR. Histomorphological features were evaluated in a second myocardial sample from LVH and HF groups.
Results:
Whereas the expression of native PPARalpha protein was lower (p<0.05) in LVH and HF groups than in the HT group, truncated PPARalpha protein was overexpressed (p<0.001) in the HF group as compared with LVH and HT groups. The mRNA expression of native and truncated PPARalpha was similar in the three groups of hypertensives. In addition, a progressive decrease (p for trend<0.05) in the two PPARalpha target genes mRNA expression was observed among HT, LVH and HF groups. The amount of truncated PPARalpha protein correlates directly with cardiomyocytes apoptosis and inversely with cardiomyocytes density in patients with HHD. In addition, the expression of truncated PPARalpha protein was directly correlated with left ventricular volumes, and inversely with ejection fraction in all hypertensives.
Conclusions:
These findings suggest that post-transcriptional regulation of PPARalpha isoforms is altered in patients with HHD, namely in those developing HF. An excess of the truncated inhibitory isoform may be involved in hypertensive left ventricular failure and remodeling.
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