Cannabidiol may prevent the development of congestive hepatopathy secondary to right ventricular hypertrophy associated with pulmonary hypertension in rats

pubmed logo

“Background: Pulmonary hypertension (PH) can cause right ventricular (RV) failure and subsequent cardiohepatic syndrome referred to as congestive hepatopathy (CH). Passive blood stasis in the liver can affect inflammation, fibrosis, and ultimately cirrhosis. Cannabidiol (CBD) has many beneficial properties including anti-inflammatory and reduces RV systolic pressure and RV hypertrophy in monocrotaline (MCT)-induced PH in rats. Thus, it suggests that CBD may have the potential to limit CH development secondary to RV failure. The present study aimed to determine whether chronic administration of CBD can inhibit the CH secondary to RV hypertrophy associated with MCT-induced PH.

Methods: The experiments involved rats with and without MCT-induced PH. CBD (10 mg/kg) or its vehicle was administered once daily for 3 weeks after MCT injection (60 mg/kg).

Results: Monocrotaline administration increased the liver/body weight ratio. In histology examinations, we observed necrosis and vacuolar degeneration of hepatocytes as well as sinusoidal congestion. In biochemical studies, we observed increased levels of nuclear factor-κappa B (NF-κB), tumour necrosis factor-alpha (TNA-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6). CBD administration to PH rats reduced the liver/body weight ratio, improved the architecture of the liver, and inhibited the formation of necrosis. Cannabidiol also decreased the level of NF-κB, TNF-α, IL-1β and IL-6.

Conclusions: The studies show that CBD can protect the liver from CH probably through attenuating PH, protective effects on the RV, and possibly direct anti-inflammatory effects on liver tissue through regulation of the NF-κB pathway.”

“In conclusion, we confirmed that the NF-κB pathway may be involved in the development of CH, especially at an early stage. Furthermore, the studies presented show that CBD can protect the liver from CH probably through attenuating PH, protective effects on the RV, and possibly direct anti-inflammatory effects on liver tissue through regulation of the NF-κB pathway. In addition, like other authors, we confirm that CBD did not cause any adverse changes in the liver of healthy rats, demonstrating its high safety potential.”

Exploring the Possible Role of Cannabinoids in Managing Post-Cardiac Surgery Complications: A Narrative Review of Preclinical Evidence and a Call for Future Research Directions

pubmed logo

“Open-heart surgery with cardiopulmonary bypass (CPB) often leads to complications including pain, systemic inflammation, and organ damage. Traditionally managed with opioids, these pain relief methods bring potential long-term risks, prompting the exploration of alternative treatments.

The legalization of cannabis in various regions has reignited interest in cannabinoids, such as CBD, known for their anti-inflammatory, analgesic, and neuroprotective properties. Historical and ongoing research acknowledges the endocannabinoid system’s crucial role in managing physiological processes, suggesting cannabinoids could offer therapeutic benefits in post-surgical recovery.

Specifically, CBD has shown promise in managing pain, moderating immune responses, and mitigating ischemia/reperfusion injury, underscoring its potential in postoperative care. However, the translation of these findings into clinical practice faces challenges, highlighting the need for extensive research to establish effective, safe cannabinoid-based therapies for patients undergoing open-heart surgery.

This narrative review advocates for a balanced approach, considering both the therapeutic potential of cannabinoids and the complexities of their integration into clinical settings.”

Investigation of neuroprotective and therapeutic effects of cannabidiol in an acute coronary syndrome model

pubmed logo

“Purpose: The ischemia-reperfusion (I/R) injury seen in the heart can cause severe damage to essential organs such as the brain. Cannabidiol (CBD) obtained from Cannabis sativa is used today to treat various diseases. This study aimed to demonstrate CBD’s neuroprotective and therapeutic properties in rats with brain damage caused by I/R in the heart.

Materials: Rats were divided into four groups; sham, I/R, I/R + Prophylactic CBD, and I/R + Therapeutic CBD. End of the experiment, brain tissues were collected for biochemical, histopathological, and genetic examinations.

Results: I/R damage increased the number of degenerative neurons, caspase-3 and TNF-α immunoexpression, total oxidant status levels, and oxidative stress index. Both prophylactic and therapeutic CBD administration reduced these increased values. In addition, the relative fold changes of AMPK, PGC-1α, SIRT1, and Bcl 2 decreased in the I/R group, and the relative fold change of Bax increased, which are indicators of ER stress and apoptosis. Both administrations of CBD reversed these genes’ relative fold changes.

Conclusion: CBD can be protective against brain injury caused by cardiac I/R damage through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.”

“Cannabidiol protects brain from damage by activating the AMPK/SIRT1/PGC-1α pathway.”

Cannabidiol protects against acute aortic dissection by inhibiting macrophage infiltration and PMAIP1-induced vascular smooth muscle cell apoptosis

pubmed logo

“Acute aortic dissection (AAD) progresses rapidly and is associated with high mortality; therefore, there remains an urgent need for pharmacological agents that can protect against AAD. Herein, we examined the therapeutic effects of cannabidiol (CBD) in AAD by establishing a suitable mouse model. In addition, we performed human AAD single-cell RNA sequencing and mouse AAD bulk RNA sequencing to elucidate the potential underlying mechanism of CBD. Pathological assays and in vitro studies were performed to verify the results of the bioinformatic analysis and explore the pharmacological function of CBD.

In a β-aminopropionitrile (BAPN)-induced AAD mouse model, CBD reduced AAD-associated morbidity and mortality, alleviated abnormal enlargement of the ascending aorta and aortic arch, and suppressed macrophage infiltration and vascular smooth muscle cell (VSMC) apoptosis. Bioinformatic analysis revealed that the pro-apoptotic gene PMAIP1 was highly expressed in human and mouse AAD samples, and CBD could inhibit Pmaip1 expression in AAD mice. Using human aortic VSMCs (HAVSMCs) co-cultured with M1 macrophages, we revealed that CBD alleviated HAVSMCs mitochondrial-dependent apoptosis by suppressing the BAPN-induced overexpression of PMAIP1 in M1 macrophages. PMAIP1 potentially mediates HAVSMCs apoptosis by regulating Bax and Bcl2 expression. Accordingly, CBD reduced AAD-associated morbidity and mortality and mitigated the progression of AAD in a mouse model. The CBD-induced effects were potentially mediated by suppressing macrophage infiltration and PMAIP1 (primarily expressed in macrophages)-induced VSMC apoptosis.

Our findings offer novel insights into M1 macrophages and HAVSMCs interaction during AAD progression, highlighting the potential of CBD as a therapeutic candidate for AAD treatment.”

Cannabidiol Alleviates Perfluorooctanesulfonic Acid-Induced Cardiomyocyte Apoptosis by Maintaining Mitochondrial Dynamic Balance and Energy Metabolic Homeostasis

pubmed logo

“Perfluorooctanesulfonic acid (PFOS), a fluorine-containing organic compound, can be widely detected in the environment and living organisms. Accumulating evidence has shown that PFOS breaks through different biological barriers resulting in cardiac toxicity, but the underlying molecular mechanisms remain unclear.

Cannabidiol (CBD) is a nonpsychoactive cannabinoid without potential adverse cardiotoxicity and has antioxidant and anti-inflammatory properties that reduce multiorgan damage and dysfunction.

For these reasons, the aim of this study was to research how PFOS caused heart injury and whether CBD could attenuate PFOS-induced heart injury.

Mice were fed PFOS (5 mg/kg) and/or CBD (10 mg/kg) in vivo. In vitro, H9C2 cells were intervened with PFOS (200 μM) and/or CBD (10 μM). After PFOS exposure, oxidative stress levels and the mRNA and protein expression of apoptosis-related markers increased distinctly, accompanied by mitochondrial dynamic imbalance and energy metabolism disorders in mouse heart and H9C2 cells. Moreover, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, acridine orange/ethidium bromide staining and Hoechst 33258 staining signaled that the number of apoptotic cells increased after exposure to PFOS.

Noteworthy, CBD simultaneous treatment alleviated a series of damages caused by PFOS-mediated oxidative stress.

Our results demonstrated that CBD could alleviate PFOS-induced mitochondrial dynamics imbalance and energy metabolism disorder causing cardiomyocyte apoptosis by improving the antioxidant capacity, suggesting that CBD may represent a novel cardioprotective strategy against PFOS-induced cardiotoxicity.

Our findings facilitate the understanding of the cardiotoxic effects of PFOS and the important role of CBD in protecting cardiac health.”

Research progress in the management of vascular disease with cannabidiol: a review

pubmed logo

“The morbidity and mortality rates associated with vascular disease (VD) have been gradually increasing. Currently, the most common treatment for VD is surgery, with the progress in drug therapy remaining slow. Cannabidiol (CBD) is a natural extract of Cannabis sativa L. with sedative, analgesic, and nonaddictive properties. CBD binds to 56 cardiovascular-related receptors and exerts extensive regulatory effects on the cardiovascular system, making it a potential pharmacological agent for the management of VD. However, most CBD studies have focused on neurological and cardiac diseases, and research on the management of VD with CBD is still rare. In this review, we summarize the currently available data on CBD in the management of VD, addressing four aspects: the major molecular targets of CBD in VD management, pharmacokinetic properties, therapeutic effects of CBD on common VDs, and side effects. The findings indicate that CBD has anti-anxiety, anti-oxidation, and anti-inflammatory properties and can inhibit abnormal proliferation and apoptosis of vascular smooth muscle and endothelial cells; these effects suggest CBD as a therapeutic agent for atherosclerosis, stress-induced hypertension, diabetes-related vasculopathy, ischemia-reperfusion injury, and vascular damage caused by smoking and alcohol abuse. This study provides a theoretical basis for further research on CBD in the management of VD.”

Cannabis Use and Incident Atrial Fibrillation in a Longitudinal Cohort

pubmed logo

“Background: Cannabis use is increasing worldwide. While prior studies have reported an association between cannabis use and a higher risk of atrial fibrillation (AF), most were cross-sectional and generally relied on diagnostic coding to identify cannabis users, which may not be representative of the typical, recreational cannabis user.

Objective: To examine the association between recreational cannabis use and lifetime AF risk.

Methods: We evaluated the AF risk of participants of the UK Biobank cohort who completed the cannabis use lifestyle questionnaire. Cannabis exposure was categorized as “Occasional Use” for less than 100 times used, “Frequent Use” for more than 100 times used, and “Never” users. AF events were identified using International Classification of Diseases (ICD) codes. Cox models were used to estimate the hazard ratios (HR) between cannabis use and incident AF and were subsequently adjusted for age, sex, race, alcohol, coffee, smoking, education, and baseline cardiovascular comorbidities.

Results: A total of 150,554 participants (mean 63.4 ± 7.7 years, 57.4% female, and 22.2% using cannabis at least once) were followed for a mean 6.1 ± 0.6 years. After multivariable adjustment, there were no statistically significant differences in incident AF among occasional users (HR 0.98, 95% CI 0.89 to 1.08) nor frequent users (HR 1.03, 95% CI 0.81 to 1.32) compared to never users.

Conclusions: Among a large, prospective cohort, there was no evidence that cannabis use was associated with a higher risk of incident AF. An evaluation of cannabis ingestion methods and quantification was not possible using the current dataset.”

Impacts of delta 9-tetrahydrocannabinol against myocardial ischemia/reperfusion injury in diabetic rats: Role of PTEN/PI3K/Akt signaling pathway

pubmed logo

“Despite the current optimal therapy, patients with myocardial ischemia/reperfusion (IR) injury still experience a high mortality rate, especially when diabetes mellitus is present as a comorbidity. Investigating potential treatments aimed at improving the outcomes of myocardial IR injury in diabetic patients is necessary. Our objective was to ascertain the cardioprotective effect of delta 9-tetrahydrocannabinol (THC) against myocardial IR injury in diabetic rats and examine the role of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in mediating this effect. Diabetes was induced in male Wistar rats (8-10 weeks old, 200-250 g; n = 60) by a single injection of streptozotocin. The duration of the diabetic period was 10 weeks. During the last 4 weeks of diabetic period, rats were treated with THC (1.5 mg/kg/day; intraperitoneally), either alone or in combination with LY294002, and then underwent IR intervention. After 24 h of reperfusion, infarct size, cardiac function, lactate dehydrogenase (LDH) and cardiac-specific isoform of troponin-I (cTn-I) levels, myocardial apoptosis, oxidative stress markers, and expression of PTEN, PI3K, and Akt proteins were evaluated. THC pretreatment resulted in significant improvements in infarct size and cardiac function and decreases in LDH and cTn-I levels (P < 0.05). It also reduced myocardial apoptosis and oxidative stress, accompanied by the downregulation of PTEN expression and activation of the PI3K/Akt signaling pathway (P < 0.05). LY294002 pretreatment abolished the cardioprotective action of THC. This study revealed the cardioprotective effects of THC against IR-induced myocardial injury in diabetic rats and also suggested that the mechanism may be associated with enhanced activity of the PI3K/Akt signaling pathway through the reduction of PTEN phosphorylation.”

“Delta 9-tetrahydrocannabinol (THC) is the main psychoactive component of cannabis and has been shown to have potential therapeutic effects in various medical conditions. THC has been shown to have anti-inflammatory and antioxidant properties, which may reduce the inflammation and oxidative stress associated with myocardial IR injury.[ Recent studies have suggested that THC improves glucose metabolism and insulin sensitivity and reduces blood glucose concentrations, oxidative stress, and inflammation associated with diabetic cardiomyopathy.”;year=2023;volume=66;issue=6;spage=446;epage=455;aulast=Zhao

Cannabis use and atherosclerotic cardiovascular disease: a Mendelian randomization study

pubmed logo

“Background: Association between cannabis use and development of atherosclerotic cardiovascular disease (ASCVD) is inconsistent and challenging to interpret, given existing study limitations.

Methods: Sixty five independent single-nucleotide polymorphisms (SNPs), obtained from a genome-wide association study on lifetime cannabis use, were employed as genetic instruments to estimate the effects of genetically indexed cannabis use on risk of coronary artery disease (CAD) and acute ischemic stroke (IS) using a two-sample Mendelian randomization (MR) approach. Summary statistics on CAD (CARDIoGRAMplusC4D; 60,801 cases and 123,504 controls) and IS (MEGASTROKE; 34,217 cases and 406,111 controls) were obtained separately. A comprehensive review of the observational literature on cannabis use and CAD or IS was also performed and contrasted with MR results.

Results: There was no causal effect of cannabis use on the risk of CAD (odds ratio (OR) per ever-users vs. never-users 0.93; 95% confidence interval (CI), 0.83 to 1.03) or IS (OR 1.05; 95%CI, 0.93 to 1.19). Sensitivity analyses yielded similar results, and no heterogeneity and directional pleiotropy was observed. Our meta-analysis of observational studies showed no significant association between ever use of cannabis with risk of CAD (k = 6 studies; ORpooled = 1.23, 95%CI 0.78 to 1.69), nor with IS (k = 6 studies; ORpooled = 1.22, 95%CI 0.95 to 1.50).

Conclusion: Using a genetic approach approximating a clinical trial does not provide evidence consistent with a causal effect of genetic predisposition to cannabis use on CAD or IS development. Further studies are needed to replicate our findinds, an to investigate more precisely the risk of ASCVD in relation to the quantity, type, route of administration, or the age at exposure to cannabis.”

Cannabidiol represses miR-143 to promote cardiomyocyte proliferation and heart regeneration after myocardial infarction

pubmed logo

“Mammalian heart is capable to regenerate almost completely early after birth through endogenous cardiomyocyte proliferation. However, this regenerative capacity diminishes gradually with growth and is nearly lost in adulthood. Cannabidiol (CBD) is a major component of cannabis and has various biological activities to regulate oxidative stress, fibrosis, inflammation, and cell death. The present study was conducted to investigate the pharmacological effects of CBD on heart regeneration in post-MI mice. MI models in adult mice were constructed via coronary artery ligation, which were administrated with or without CBD. Our results demonstrate that systemic administration (10 mg/kg) of CBD markedly increased cardiac regenerative ability, reduced infarct size, and restored cardiac function in MI mice. Consistently, in vitro study also showed that CBD was able to promote the proliferation of neonatal cardiomyocytes. Mechanistically, the expression of miR-143-3p related to cardiomyocyte proliferation was significantly down-regulated in CBD-treated cardiomyocytes, while the overexpression of miR-143-3p inhibited cardiomyocyte mitosis and eliminated CBD-induced cardiomyocyte proliferation. Moreover, CBD enhanced the expression of Yap and Ctnnd1, which were demonstrated as the target genes of miR-143-3p. Silencing of Yap and Ctnnd1 hindered the proliferative effects of CBD. We further revealed that inhibition of the cannabinoid receptor 2 impeded the regulatory effect of CBD on miR-143-3p and its downstream target Yap/Ctnnd1, which ultimately eliminated the pro-proliferative effect of CBD on neonatal and adult cardiomyocytes. Taken together, CBD promotes cardiomyocyte proliferation and heart regeneration after MI via miR-143-3p/Yap/Ctnnd1 signaling pathway, which provides a new strategy for cardiac repair in adult myocardium.”

“Cannabidiol (CBD)-an abundant component of cannabis with no psychoactive or cognitive effect has been shown to have extensive therapeutic properties including neuroprotection, anti-inflammation, anti-tumor and analgesic effects. In addition, multiple lines of evidence indicated that CBD is a potent protective agent against cardiovascular disease.”