Combination of folic acid with nifedipine is completely effective in attenuating aortic aneurysm formation as a novel oral medication

Huang, Kai; Wu, Yusi; Zhang, Yixuan; Youn, Ji Youn; Cai, Hua

doi:10.1016/j.redox.2022.102521

Cited by 9 publications

(13 citation statements)

References 27 publications

(151 reference statements)

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“…These data seem to share some similarities with our previous findings that an endothelial-specific deficiency in DHFR underlies development of systematic disorders of hypertension and aortic aneurysms in Ang II infused WT mice, hph-1 mice, and apoE null mice. 21,23,24,32,[34][35][36][37][38][39][40][41] This observation also further aligns with the robust therapeutic effect of endothelialspecific DHFR transgenesis in protecting against PH in the tg-EC-DHFR mice. Of note, hypoxia treatment of the DHFR knockout mice showed no additional worsening in PH phenotypes, indicating an intrinsic role of DHFR deficiency in mediating hypoxia-induced PH.…”

Section: Discussionsupporting

confidence: 71%

“…We and others have demonstrated that endothelial DHFR plays a key role in preserving eNOS coupling activity to attenuate hypertension, aortic aneurysms, and diabetic vascular complications. [21][22][23][24]27,32,[34][35][36][37][38][39][40][41] We have generated a novel endothelial-specific DHFR transgenic mouse strain (tg-EC-DHFR) to investigate the potential therapeutic effect on PH of endothelialspecific DHFR overexpression in vivo (Figures . 3A-3F).…”

Section: Transgenesis Of Dhfr In the Endothelium Protects Against Ph ...mentioning

confidence: 99%

“…When tetrahydrobiopterin bioavailability is low consequent to oxidative inactivation and a deficiency in its salvage enzyme DHFR, electrons are diverted to molecular oxygen rather than to L-arginine, transforming eNOS into a superoxide anion-generating pro-oxidant enzyme, denoted as uncoupled eNOS. 21–41 This transformation of eNOS has been observed in several in vitro models, animal models, and human patients with cardiovascular diseases, including hypertension, aortic aneurysms, atherosclerosis, diabetic vascular complications, cardiac ischemia reperfusion injury, and heart failure. 21–41 In view of the critical role of endothelial dysfunction in initiating the pathophysiological processes of PH, we hypothesize that uncoupling of eNOS might have a direct causal role in the development of PH, which might be used to establish an animal model that resembles human PH or idiopathic PH.…”

mentioning

confidence: 96%

“…21–41 This transformation of eNOS has been observed in several in vitro models, animal models, and human patients with cardiovascular diseases, including hypertension, aortic aneurysms, atherosclerosis, diabetic vascular complications, cardiac ischemia reperfusion injury, and heart failure. 21–41 In view of the critical role of endothelial dysfunction in initiating the pathophysiological processes of PH, we hypothesize that uncoupling of eNOS might have a direct causal role in the development of PH, which might be used to establish an animal model that resembles human PH or idiopathic PH.…”

mentioning

confidence: 96%

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Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR

Murugesan,

Zhang,

Huang

et al. 2024

Circulation Research

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BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting in right heart failure. METHODS: Here, we show that direct targeting of the endothelium to eNOS (endothelial nitric oxide synthase) with DAHP (2,4-diamino 6-hydroxypyrimidine; an inhibitor of GTP cyclohydrolase 1, the rate-limiting synthetic enzyme for the critical eNOS cofactor tetrahydrobiopterin) induces human-like, time-dependent progression of PH phenotypes in mice. RESULTS: Critical phenotypic features include elevation in mean pulmonary arterial pressure, right ventricular systolic blood pressure, and right ventricular/(LV+S) ratio; extensive vascular remodeling of pulmonary arterioles with increased medial thickness/perivascular collagen deposition and increased expression of PCNA (proliferative cell nuclear antigen) and alpha-actin; increased total and mitochondrial superoxide production, reduced tetrahydrobiopterin, and nitric oxide bioavailabilities; and formation of an array of human-like vascular lesions. Intriguingly, novel in-house generated endothelial-specific dihydrofolate reductase (DHFR) transgenic mice were completely protected from the pathophysiological and molecular features of PH upon DAHP treatment or hypoxia. Furthermore, DHFR overexpression with a pCMV-DHFR plasmid transfection in mice after initiation of DAHP treatment completely reversed PH phenotypes. DHFR knockout mice spontaneously developed PH at baseline and had no additional deterioration in response to hypoxia, indicating an intrinsic role of DHFR deficiency in causing PH. RNA-sequencing experiments indicated great similarity in gene regulation profiles between the DAHP model and patients with human PH. Conclusions: Taken together, these results establish a novel human-like murine model of PH that has long been lacking in the field, which can be broadly used for future mechanistic and translational studies. These data also indicate that targeting endothelial DHFR deficiency represents a novel and robust therapeutic strategy for the treatment of PH.

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Section: Discussionsupporting

confidence: 71%

Section: Transgenesis Of Dhfr In the Endothelium Protects Against Ph ...mentioning

confidence: 99%

mentioning

confidence: 96%

mentioning

confidence: 96%

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Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR

Murugesan,

Zhang,

Huang

et al. 2024

Circulation Research

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“…To validate this, we carried out pull‐down experiments and found that folic acid was linked to both TRPV4 and K Ca 3.1 proteins (Figures 4b and S10D), with the binding sites being Arg186, Pro188, Arg232 on TRPV4 and Thr35, Leu39 on K Ca 3.1 (Figure S9B). Next, the mice were given folic acid (15 mg kg −1 ) daily (Gao et al, 2012; Huang et al, 2022) for 5 weeks, with similar serum folic acid concentration at the beginning of the experiment (Figure S12a). As our results showed (Figure 4c), folic acid restored the TRPV4‐K Ca 3.1 coupling in CAECs of HFD mice, but did not change the expression of TRPV4 or K Ca 3.1 protein (Figure S12b).…”

Section: Resultsmentioning

confidence: 99%

Functional role of coupling the endothelial TRPV4 and K_Ca3.1 channels in regulating coronary vascular tone

Mao

et al. 2023

British J Pharmacology

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Background and Purpose: High-fat diet (HFD) induces dysregulated pathways in coronary artery endothelial cells (CAECs), which leads to altered regulation of vascular tone, tissue perfusion and increases the risk of coronary artery diseases. Ca 2+ -activated K + (K Ca ) channels are known to be associated with transient receptor potential (TRP) channels, which are important for regulating endothelial function. But how TRPV4 channels interacts with K Ca channels in regulating coronary vascular tone in HFD mice requires further exploration.Experimental Approach: TRPV4 channel activity was assessed by fluorescent Ca 2+ imaging. Interactions between TRPV4 and K Ca 3.1 channels were verified by coimmunoprecipitation and immunofluorescence resonance energy transfer (FRET), and their binding site was found by site-directed mutagenesis. Endothelium-specific TRPV4 knockout (TRPV4 EC À/À ) mice were used to study the effect of the interactions between TRPV4-K Ca 3.1 channels on coronary vascular tone. Coronary blood flow was measured by Doppler ultrasound device.Key Results: TRPV4 channels were involved in regulating coronary vascular tone, through coupling with a Ca 2+ -sensitive K + channel (K Ca 3.1) in CAECs, affecting vasodilation and coronary blood flow. In mice fed a HFD diet, the coupling was damaged by a high concentration of plasma 1-heptadecanoyl-2-hydroxy-sn-glycero-3-phosphocholine. Using a bridging approach, we then identified folic acid as an effective drug to repair the uncoupled TRPV4-K Ca 3.1 channels and to improve coronary arterial function. Conclusion and Implications:Our data highlight the importance of coupling between TRPV4 and K Ca 3.1 channels in the regulation of coronary vascular tone and provide a novel strategy for developing new drugs to reduce the incidence of cardiovascular events.

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Mechanical stress induced mitochondrial dysfunction in cardiovascular diseases: Novel mechanisms and therapeutic targets

Ren,

Hu,

Jiang

et al. 2024

Biomedicine & Pharmacotherapy

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Combination of folic acid with nifedipine is completely effective in attenuating aortic aneurysm formation as a novel oral medication

Cited by 9 publications

References 27 publications

Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR

Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR

Functional role of coupling the endothelial TRPV4 and K_Ca3.1 channels in regulating coronary vascular tone

Mechanical stress induced mitochondrial dysfunction in cardiovascular diseases: Novel mechanisms and therapeutic targets

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Combination of folic acid with nifedipine is completely effective in attenuating aortic aneurysm formation as a novel oral medication

Cited by 9 publications

References 27 publications

Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR

Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR

Functional role of coupling the endothelial TRPV4 and KCa3.1 channels in regulating coronary vascular tone

Mechanical stress induced mitochondrial dysfunction in cardiovascular diseases: Novel mechanisms and therapeutic targets

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Product

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About

Functional role of coupling the endothelial TRPV4 and K_Ca3.1 channels in regulating coronary vascular tone