Folic acid mitigated cardiac dysfunction by normalizing the levels of tissue inhibitor of metalloproteinase and homocysteine-metabolizing enzymes postmyocardial infarction in mice

Qipshidze, Natia; Tyagi, Neetu; Sen, Utpal; Givvimani, Srikanth; Metreveli, Naira; Lominadze, David; Tyagi, Suresh C.

doi:10.1152/ajpheart.00577.2010

Cited by 22 publications

(23 citation statements)

References 52 publications

(61 reference statements)

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“…We found a decrease in TIMP-4 in RV of PAC mice. Interestingly, the level of TIMP-4 was restored in PAC animals given folic acid supplementation, suggesting an effect of folic acid on expression TIMPs that confirms our earlier findings (38). The differential role of MMP-2 versus MMP-9 has been suggested (10,13).…”

Section: Discussionsupporting

confidence: 87%

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

Qipshidze

Tyagi

Metreveli

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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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.

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Section: Discussionsupporting

confidence: 87%

“…We have shown that folic acid decreases collagen accumulation in hypertensive hearts (38). Others have indicated that folic acid supplementation lowers collagen and scar formation (12).…”

Section: Discussionmentioning

confidence: 90%

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

Qipshidze

Tyagi

Metreveli

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…In animals, FA has been demonstrated to significantly improve myocardial function after myocardial infarction in rats (106) and to reduce myocardial ischemic dysfunction and postreperfusion injury in mice (89). However, recent clinical trials have failed to demonstrate a benefit of long-term use of FA (15,75) that can be explained by too low of a dosage (89).…”

Section: The Role Of Folic Acid For No Availabilitymentioning

confidence: 99%

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Zhang¹,

Janssens

Wingler

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Zhang Y, Janssens SP, Wingler K, Schmidt HH, Moens AL. Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy. Am J Physiol Heart Circ Physiol 301: H634 -H646, 2011. First published May 27, 2011 doi:10.1152/ajpheart.01315.2010.-The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a promising therapeutic intervention. In particular, modulating eNOS, e.g., through increasing the bioavailability of its substrate and cofactors, enhancing its transcription, and interfering with other modulators of eNOS pathway, such as netrin-1, has a high potential for effective treatments of cardiovascular diseases. This review provides an overview of the possibilities for modulating eNOS and how this may be translated to the clinic in addition to describing the genetic models used to study eNOS modulation.endothelial nitric oxide synthase uncoupling; modulators; superoxide; tetrahydrobiopterin; enhancers; nitric oxide donors THE REVALENCE AND SEVERITY of incipient or overt cardiovascular diseases associated with reduced nitric oxide (NO) bioavailability has resulted in efforts to restore and conserve adequate NO signaling in the heart and blood vessels through therapeutic interventions. In the cardiovascular system, the signaling molecule NO, which is produced by the enzyme endothelial NO synthase (eNOS, NOS3), has a crucial role in maintaining normal vascular function, mediated by its vasodilating capacity and through a variety of antiatherogenic effects. eNOS is not only expressed in endothelial cells of the heart and blood vessels, in both atrial and ventricular myocytes, but also in specialized pacemaker tissue.Uncoupling of bioactive, i.e., dimeric eNOS to an inactive monomeric form (73) is caused by oxidative stress, which reduces the bioavailability of tetrahydrobiopterin (BH 4 ), an essential cofactor of eNOS. In this uncoupled state, NADPH consumption and oxygen reduction are uncoupled from L-arginine oxidation and NO formation with a subsequently decreased NO production and increased superoxide generation (157). eNOS generated superoxide, further oxidizes BH 4 , and hence enhances the uncoupling of eNOS. However, it is unclear which source of superoxide initiates eNOS uncoupling.Uncoupling of eNOS has been described in 1) situations associated with endothelial dysfunction such as atherosclerosis (3, 70), diabetes mellitus (135), ischemia-reperfusion (I/R) injury (35,138), hypertension (68), and chronic flow overload (78); 2) cardiac hypertrophy with ventricular remodeling (133); and 3) diastolic heart failure (149). eNOS also uncouples physiologically. For example, eNOS may uncouple postnatal in the lung, possibly leading to a developmental adaptation of the pulmonary vascular system to produce reactive oxygen species (ROS) (81). In addition, it ...

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“…The methylation of nucleic acids and demethylation of methionine produce homocysteine, and levels of homocysteine increase following myocardial infarction (Moens et al, 2008). Studies by Qipshidze et al showed improved myocardial function following MI with folic acid supplementation; folic acid may attenuate this build up of homocysteine by remethylating the homocysteine to methionine, through 5-methylene tetrahydrofolate reductase, reducing the plasma concentrations of homocysteine by up to 25% (Qipshidze et al, 2010).…”

Section: Methylationmentioning

confidence: 99%

Cardioprotection requires flipping the ‘posttranslational modification’ switch

et al. 2012

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Folic acid mitigated cardiac dysfunction by normalizing the levels of tissue inhibitor of metalloproteinase and homocysteine-metabolizing enzymes postmyocardial infarction in mice

Cited by 22 publications

References 52 publications

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

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

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Cardioprotection requires flipping the ‘posttranslational modification’ switch

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