Autophagy mechanism of right ventricular remodeling in murine model of pulmonary artery constriction.

Abstract

Although right ventricular failure (RVF) is the hallmark of pulmonary arterial hypertension (PAH), the mechanism of RVF is unclear. Development of PAH-induced RVF is associated with an increased reactive oxygen species (ROS) production. Increases in oxidative stress lead to generation of nitro-tyrosine residues in tissue inhibitor of metalloproteinase (TIMPs) and liberate active matrix metalloproteinase (MMPs). To test the hypothesis that an imbalance in MMP-to-TIMP ratio leads to interstitial fibrosis and RVF and whether the treatment with folic acid (FA) alleviates ROS generation, maintains MMP/TIMP balance, and regresses interstitial fibrosis, we used a mouse model of pulmonary artery constriction (PAC). After surgery mice were given FA in their drinking water (0.03 g/l) for 4 wk. Production of ROS in the right ventricle (RV) was measured using oxidative fluorescent dye. The level of MMP-2, -9, and -13 and TIMP-4, autophagy marker (p62), mitophagy marker (LC3A/B), collagen interstitial fibrosis, and ROS in the RV wall was measured. RV function was measured by Millar catheter. Treatment with FA decreased the pressure to 35 mmHg from 50 mmHg in PAC mice. Similarly, RV volume in PAC mice was increased compared with the Sham group. A robust increase of ROS was observed in RV of PAC mice, which was decreased by treatment with FA. The protein level of MMP-2, -9, and -13 was increased in RV of PAC mice in comparison with that in the sham-operated mice, whereas supplementation with FA abolished this effect and mitigated MMPs levels. The protein level of TIMP-4 was decreased in RV of PAC mice compared with the Sham group. Treatment with FA helped PAC mice to improve the level of TIMP-4. To further support the claim of mitophagy occurrence during RVF, the levels of LC3A/B and p62 were measured by Western blot and immunohistochemistry. LC3A/B was increased in RV of PAC mice. Similarly, increased p62 protein level was observed in RV of PAC mice. Treatment with FA abolished this effect in PAC mice. These results suggest that FA treatment improves MMP/TIMP balance and ameliorates mitochondrial dysfunction that results in protection of RV failure during pulmonary hypertension.

• Authors: Natia Qipshidze, Neetu Tyagi, Naira Metreveli, David Lominadze, Suresh C Tyagi
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 302 Issue 3 Pg. H688-96 (Feb 01 2012) ISSN: 1522-1539 [Electronic] United States
• PMID: 22101525 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Biomarkers
• Reactive Oxygen Species
• Tissue Inhibitor of Metalloproteinases
• tissue inhibitor of metalloproteinase-4
• Vitamin B Complex
• Folic Acid
• Matrix Metalloproteinase 13
• Mmp13 protein, mouse
• Matrix Metalloproteinase 2
• Mmp2 protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Autophagy (drug effects, physiology)
• Biomarkers (metabolism)
• Disease Models, Animal
• Folic Acid (pharmacology)
• Heart Ventricles (metabolism, pathology, physiopathology)
• Hypertension, Pulmonary (drug therapy, metabolism, pathology, physiopathology)
• Hypertrophy, Right Ventricular (drug therapy, metabolism, pathology, physiopathology)
• Male
• Matrix Metalloproteinase 13 (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Pulmonary Artery (metabolism, pathology, physiopathology)
• Reactive Oxygen Species (metabolism)
• Tissue Inhibitor of Metalloproteinases (metabolism)
• Ventricular Remodeling (drug effects, physiology)
• Vitamin B Complex (pharmacology)