Results: We found that CBD reversed the pathological changes observed in both Sugen-hypoxia and monocrotaline-induced PAH rodent models in a cannabinoid receptors-independent manner. Our results also demonstrated that CBD significantly inhibited the PASMCs’ proliferation in PAH mice with less inflammation and reactive oxygen species levels. Moreover, CBD alleviated rodent PAH by recovering mitochondrial energy metabolism, normalizing the hypoxia-induced oxidant stress, reducing the lactate overaccumulation and abnormal glycolysis.
Methods: In this study, the effects of CBD in PAH were determined by analyzing its preventive and therapeutic actions in PAH rodent models in vivo and PASMCs’ proliferation test in vitro. Additionally, CBD’s roles in mitochondrial function and oxidant stress were also assessed in PASMCs.
Lu X, Zhang J, Liu H, Ma W, Yu L, Tan X, Wang S, Ren F, Li X, Li X. Cannabidiol attenuates pulmonary arterial hypertension by improving vascular smooth muscle cells mitochondrial function. Theranostics 2021; 11(11):5267-5278. doi:10.7150/thno.55571. Available from https://www.thno.org/v11p5267.htm
Rationale: Pulmonary arterial hypertension (PAH) is a chronic disease associated with enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional mitochondria, and the clinical therapeutic option for PAH is very limited. Recent studies showed that cannabidiol (CBD), a non-psychoactive constituent of cannabinoids, possessed antioxidant effect towards several cardiovascular diseases, whereas the mechanistic effect of CBD in PAH is unknown.
✉ Corresponding author: Xiangdong Li, State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China, xiangdongli68com, 86-10-62734389 (Tel/Fax).
Conclusions: Taken together, these findings confirm an important role for CBD in PAH pathobiology.
1. State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
2. Yunnan Hempmon Pharmaceuticals Co. Ltd., Beijing, 100010, China.
3. Hanma Investment Group Co., Ltd., Beijing, 100010, China.
4. Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
5. Department of Surgery, Chinese PLA General Hospital, Beijing, 100071, China.
6. Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland.
* Xiaohui Lu, Jingyuan Zhang contributed equally to this work.
Keywords: Cannabinoids, Pulmonary arterial hypertension, Antioxidant, Mitochondria networks, Glycolysis.
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PAH Life Expectancy
Major Developments in Pulmonary Hypertension Affecting Prognosis 1. Approval of
To explore the efficacy of CBD in the PAH, we established several rodent PAH models, SU-5416 (Sugen) hypoxia-induced PAH mouse models, which including the preventive model and therapeutic model, and monocrotaline (MCT)-induced PAH rat preventive model. By using a hypoxia-induced PAH preventive mouse model (with CBD treatment at 10 mg/kg and 20 mg/kg, respectively), we found that CBD at 10 mg/kg had the better efficacy to attenuate PAH phenotypes in PAH mice (Figure S2). Based on above results and other reports 28 – 31 , the effective dose of CBD in Sugen hypoxia- and MCT-induced PAH rodent models was established as 10 mg/kg.
4 Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
Right ventricular systolic pressure (RVSP) was measured with a micro-pressure transducer (Samba Preclin 420 LP transducer, Samba Sensors, Sweden). It is an invasive test called heart catheterization, the catheter was insert into the right ventricle of the mouse/rat heart along the right carotid artery, the RVSP curve and data were measured and analyzed with the BE-EH4 biological signal system (Beijing Baianji Science and technology company, China) as described previously 23 .
Vascular remodeling analysis
We also observed that CBD could regulate the genes related to oxidative stress (Hmox1, Sod1) in the normal mice PASMCs. Previous studies have also reported the strong antioxidant capacity of CBD, and CBD can upregulate Hmox1, activate the NRF2-keap1 pathway and normalize the cell functions under the oxidant stress 36 . Based on these results, we could speculate that CBD had the efficacy to maintain the mitochondrial homeostasis in both patho-/physiological conditions.
1 State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Next, we compared it with the other compounds that used in the first-line therapy against PAH, such as bosentan and beraprost sodium 32 . The results illustrated that all these three compounds could attenuate the elevated RVSP and RVH in the Sugen hypoxia-induced PAH mice. Efficacies among CBD, bosentan and beraprost sodium were very similar, and no significant difference was observed in the prevention of Sugen-hypoxia induced PAH (Figure S4A-B). Taken together, these results demonstrated that CBD could inhibit the development of PAH and its effect was comparable with the first-line PAH drugs in rodent models.
After paraffin embedding and sectioning, the lung slides (4 μm thickness) were stained with hematoxylin and eosin (H.E.) for morphological analysis. To assess the degree of pulmonary arterial remodeling, microscopic images of Elastin van Gieson and α-smooth muscle actin-stained lung sections were captured using the Olympus BX53 microscope (Olympus, Japan). Pulmonary vascular remodeling was quantified by accessing the medial wall thickness and the percentage of muscularization as descripted previously 24 – 27 . To determine the degree of medial wall thickness, < 50 μm and > 50 μm in diameter from each lung were randomly outlined by an observer blinded to mouse group or antibody treatment. The degree of medial wall thickness, expressed as a ratio of medial area to cross sectional area (Media/CSA), were analyzed using Image J. More than 20 vessels with diameters ranging from 25 to 75 μm were counted from non-serial lung sections and categorized as either fully (i.e., with a complete medial coat of muscle), partially (i.e., with only a crescent of muscle) or non-muscularized (i.e., with no apparent muscle) 26 .