Imbalance and dysfunction of transient receptor potential channels contribute to the pathogenesis of hypertension

Intracellular Ca2+homeostasis is essential for vascular function and blood pressure regulation.Because of their unique roles in regulating intracellular Ca2+concentration and vascular function,a novel class of non-selective cation channels,called transient receptor potential(TRP)channels,have emerged at the frontier of hypertension research.Based on their role in vasculature function regulation,TRP channels can be divided into two functional subtypes:one that participates in vasoconstriction and one that participates in vasodilatation.A functional imbalance of these two subtypes of TRP channels may disturb intracellular calcium([Ca2+]i)homeostasis,and the consequent vascular dysfunction may contribute to the development of hypertension.The potential of these TRP channels as novel pharmacological targets for the treatment of human hypertension is of great interest.

Metabolic hypertension:concept and practice

Hypertension is a serious public health problem worldwide.More than 60%of the risk factors for hypertension are associated with metabolic disturbances.Metabolic abnormalities increase the risk for hypertension and cause high blood pressure.Improving metabolic disturbances is beneficial for hypertension treatment.Due to the importance of metabolic abnormalities in the pathogenesis of hypertension,we propose a concept of metabolic hypertension.In this review,we discuss and review the clinical types,pathogenesis,risk evaluation and management of metabolic hypertension.Elucidation of the mechanism of metabolic hypertension should facilitate the design of novel pharmacotherapeutics and dedicated antihypertensive manipulations.

Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity

Brown adipose tissue(BAT)is an energy-expending organ that produces heat.Expansion or activation of BAT prevents obesity and diabetes.Chronic cold exposure enhances thermogenesis in BAT through uncoupling protein 1(UCP1)activation triggered via a b-adrenergic pathway.Here,we report that the cold-sensing transient receptor potential melastatin 8(TRPM8)is functionally present in mouse BAT.Challenging brown adipocytes with menthol,a TRPM8 agonist,up-regulates UCP1 expression and requires protein kinase A activation.Upon mimicking long-term cold exposure with chronic dietary menthol application,menthol significantly increased the core temperatures and locomotor activity in wild-type mice;these effects were absent in both TRPM82/2 and UCP12/2 mice.Dietary obesity and glucose abnormalities were also prevented by menthol treatment.Our results reveal a previously unrecognized role for TRPM8,suggesting that stimulation of this channel mediates BAT thermogenesis,which could constitute a promising way to treat obesity.

Beyond Thermal Sensation: Roles of Transient Receptor Potential Vanilloid Subfamily Member 1 and Spicy Food in Cardiometabolic Diseases

The 2021 Nobel Prize in Physiology or Medicine was awarded to David Julius for his discovery of capsaicin receptors in 1997.[1]The capsaicin receptor is also called transient receptor potential vanilloid subfamily member 1(TRPV1)and belongs to the transient receptor potential channels family.TRPV1 possesses a tetrameric structure consisting of 6 transmembrane regions,a pore-shaped region between the fifth(S5)and sixth transmembrane regions(S6),a cytoplasmic amino group,and a carboxyl terminus,which is selectively permeable for cations such as H+,Na+,and Ca^(2+).[1]TRPV1 can be activated by nociceptive thermal stimulation(temperature>43℃),pH values less than 5.96,and capsaicin,a pungent component of chili peppers,and other factors including free oxygen radicals,12-lipoxygenase,20-hydroxyeicosatetraenoic acid,etc.

Obesity pandemic in China:epidemiology,burden,challenges,and opportunities

China faces a substantial burdensome pandemic of obesity.Recent data from the Chinese Centre for Disease Control and Prevention suggested that over an estimated 8.1%of Chinese adults(85 million Chinese adults)had obesity in 2018,which was three times the level in 2004.[1]To understand the trends of overweight and obesity in China,we accessed the country/territory-level year-specific data of age-standardized summary exposure value(SEV,standing for the pooled proportion among the population),deaths,and disability-adjusted life of years(DALYs)for high body mass index(BMI,high BMI was defined as the BMI level higher than theoretical minimum risk exposure level[25 kg/m2])and its associated diseases for 204 countries/territories between 1990 and 2019 using data from the Global Burden of Disease Collaborative Network.[2]Previous literature described detailed methods for the data synthesis.[3,4]Using the country/territory-level data by year,we calculated the estimated annual percentage changes(EAPCs)with 95%uncertainty intervals(UI)to estimate the annual changing patterns of age-standardized SEV,death,and DALY rates among 204 countries/territories.To compare statistics from China and other regions,we calculated the corresponding estimates from regions including global,North Africa and Middle East,Sub-Saharan Africa,Western Pacific Region,European Union,Latin America and Caribbean,and South Asia.

Activation of the bitter taste sensor TRPM5 prevents high saltinduced cardiovascular dysfunction

High salt intake is a known risk factor of cardiovascular diseases. Our recent study demonstrated that long-term high salt intake impairs transient receptor potential channel M5(TRPM5)-mediated aversion to high salt concentrations, consequently promoting high salt intake and hypertension;however, it remains unknown whether TRPM5 activation ameliorates cardiovascular dysfunction. Herein we found that bitter melon extract(BME) and cucurbitacin E(CuE), a major compound in BME, lowered high salt-induced hypertension. Long-term BME intake significantly enhanced the aversion to high salt concentrations by upregulating TRPM5 expression and function, eventually decreasing excessive salt consumption in mice. Moreover, dietary BME ameliorated high salt-induced cardiovascular dysfunction and angiotensin II-induced hypertension in vivo. The mechanistic evidence demonstrated that dietary BME inhibited high salt-induced RhoA/Rho kinase pathway overactivation, leading to reduced phosphorylation levels of myosin light chain kinase and myosin phosphatase targeting subunit 1. Furthermore, CuE inhibited vasoconstriction by attenuating L-type Ca^(2+) channel-induced Ca^(2+) influx in vascular smooth muscle cells. To summarize, our findings indicate that dietary BME has a beneficial role in antagonizing excessive salt consumption and thus appears promising for the prevention of high salt-induced cardiovascular dysfunction.

CILP-2 is a novel secreted protein and associated with insulin resistance

Genetic association studies have implicated that cartilage intermediate layer protein 2 (CILP-2) confers the risk susceptibility for type 2 diabetes (T2DM). However, it is still unknown whether CILP-2 is involved in the regulation of glucose homeostasis and insulin resistance (IR). In the current study, we initially observed that CILP-2 as a secreted protein was detected in both conditioned medium and lysates of cells transfected with an overexpressed vector. We then found that circulating CILP-2 levels had a progressive increase from normal to impaired glucose tolerance (a pre-diabetic status) and then to diabetes, which was correlated positively with waist-to-hip ratio, triglyceride, fasting blood glucose, 2-h blood glucose after glucose overload, HbA1c, fasting insulin, 2-h plasma insulin after glucose overload, and homeostasis model assessment of insulin resistance but negatively with HDL-C. CILP-2 expression was increased in the liver and muscle but decreased in adipose tissues of obese mice or T2DM patients. Furthermore, we demonstrated that CILP-2 circulating levels were affected by OGTT and Exenatide. CILP-2 overexpression resulted in impaired glucose tolerance and hepatic IR in vivo and increased PEPCK expression whereas suppressed phosphorylation of insulin receptor and Akt kinase in vitro. Based on these findings, we have identified a direct interaction between CILP-2 and PEPCK and suggested that CILP-2 plays an important role in the regulation of hepatic glucose production.