Thomas Unger

Cannabinoids (CB) are implicated in cardiovascular diseases via the two main receptor subtypes CB₁R and CB₂R. This study investigated whether cannabinoids regulate the activity of matrix metalloproteases (MMP-2, MMP-9) in vascular smooth muscle cells (VSMCs) and in cells of cardiac origin (H9c2 cell line). The influence of CB₁- and CB₂ receptor stimulation or inhibition on cell proliferation, apoptosis and glucose uptake was also evaluated. We used four compounds that activate or block CB receptors: arachidonyl-2-chloroethylamide (ACEA)—CB₁R agonist, rimonabant—CB₁R antagonist, John W. Huffman (JWH133)—CB₂R agonist and CB₂R antagonist—6-Iodopravadoline (AM630). Treatment of cells with the CB₂R agonist JWH133 decreased cytokine activated secretion of proMMP-2, MMP-2 and MMP-9, reduced Fas ligand and caspase-3-mediated apoptosis, normalized the expression of TGF-beta1 and prevented cytokine-induced increase in glucose uptake into the cell. CB₁R inhibition with rimonabant showed similar protective properties as the CB₂R agonist JWH133, but to a lesser extent. In conclusion, CB₁R and CB₂R exert opposite effects on cell glucose uptake, proteolysis and apoptosis in both VSMCs and H9c2 cells. The CB₂R agonist JWH133 demonstrated the highest protective properties. These findings may pave the way to a new treatment of cardiovascular diseases, especially those associated with extracellular matrix degradation.

Raised blood pressure (BP) is the leading cause of preventable death in the world. Yet, its global prevalence is increasing, and it remains poorly detected, treated, and controlled in both high- and low-resource settings. From the perspective of members of the International Society of Hypertension based in all regions, we reflect on the past, present, and future of hypertension care, highlighting key challenges and opportunities, which are often region-specific. We report that most countries failed to show sufficient improvements in BP control rates over the past three decades, with greater improvements mainly seen in some high-income countries, also reflected in substantial reductions in the burden of cardiovascular disease and deaths. Globally, there are significant inequities and disparities based on resources, sociodemographic environment, and race with subsequent disproportionate hypertension-related outcomes. Additional unique challenges in specific regions include conflict, wars, migration, unemployment, rapid urbanization, extremely limited funding, pollution, COVID-19-related restrictions and inequalities, obesity, and excessive salt and alcohol intake. Immediate action is needed to address suboptimal hypertension care and related disparities on a global scale. We propose a Global Hypertension Care Taskforce including multiple stakeholders and societies to identify and implement actions in reducing inequities, addressing social, commercial, and environmental determinants, and strengthening health systems implement a well-designed customized quality-of-care improvement framework.

The title of the recent editorial by Prof. Kjeldsen et al. [1] suggests that the latest guidelines of the International Society of Hypertension (ISH) [2] have introduced a drug treatment recommenda...

Rationale:Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Ang II infusion is associated with increased permeability of the blood-brain barrier (BBB) and chronic activation of microglia. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach.Methods:For this study, adultCx3Cr1^gfp/wtxThy1^yfp/0reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF-1R inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory were assessed during an Object Location task and a Morris Water Maze task (MWM). At the end of the study, microglia depletion efficacy and BBB leakages were assessed using flow cytometry and immunohistochemistry.Results:SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, but not in Ang II mice treated with PLX5622. Histological and flow cytometry analyses revealed almost complete ablation of microglia upon CSF1R inhibition, while brain resident perivascular macrophages, were reduced by 60%. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment.Conclusion:Our results show that depletion of microglia, and less so PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. This novel finding supports the critical role of brain immune cells, and most in particular microglia, in the pathogenesis of hypertension-related cognitive impairment.

Recently, AT2 receptors have been discovered on the surface of human immunocompetent cells such as monocytes. Data on regulative properties of this receptor on the cellular immune response are poor. We hypothesized that direct stimulation of the AT2 receptor mediates anti-inflammatory responses in these cells. Human monocytic THP-1 and U937 cells were stimulated with lipopolysaccharide (LPS) and the selective AT2 receptor agonist Compound 21 (C21). Expression of pro- and anti-inflammatory cytokines IL-6, IL-10, tumor necrosis factor-α (TNFα), and IL-1β were analyzed on both the transcriptional and the translational level over course of time. Treatment with C21 attenuated the expression of TNFα, IL-6, and IL-10 after LPS challenge in both cell lines in a time- and dose-dependent manner. We conclude that selective AT2 receptor stimulation acts anti-inflammatory in human monocytes. Modulation of cytokine response by AT2 receptor activation might be a beneficial and novel treatment concept in inflammatory conditions.

Blockade of the renin-angiotensin system with angiotensin II receptor blockers (ARBs) provides blood pressure (BP)-independent effects throughout the cardiovascular (CV) continuum. In the landmark ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET), telmisartan reduced CV events in patients at high CV risk, similar to the angiotensin-converting enzyme inhibitor, ramipril. This reduction in CV events is a consequence of non-BP effects on disease pathophysiology which have been demonstrated in preclinical and clinical studies. For example, telmisartan significantly reduces markers of inflammation, such as interleukin-6 and C-reactive protein, and improves markers of vascular function, such as pulse wave velocity. Both these are associated with target organ damage. Telmisartan also has numerous potentially beneficial metabolic effects in preclinical studies. Telmisartan reduces markers of renal disease and its progression, left ventricular hypertrophy, and the risk of primary or secondary atrial fibrillation. Many of these effects are shared with other RAS inhibitors. However, several studies indicate differential effects between telmisartan and other ARBs. These differences probably reflect telmisartan’s distinct pharmacologic profile, including the longest plasma half-life, high receptor-binding affinity, and highest lipophilicity of the class. These differences suggest that the results of ONTARGET do not necessarily extrapolate to other ARBs.