Pinpointing beta adrenergic receptor in ageing pathophysiology: victim or executioner? Evidence from crime scenes

G protein-coupled receptors (GPCRs) play a key role in cellular communication, allowing human cells to sense external cues or to talk each other through hormones or neurotransmitters. Research in this field has been recently awarded with the Nobel Prize in chemistry to Robert J. Lefkowitz and Brian K. Kobilka, for their pioneering work on beta adrenergic receptors (βARs), a prototype GPCR. Such receptors, and β2AR in particular, which is extensively distributed throughout the body, are involved in a number of pathophysiological processes. Moreover, a large amount of studies has demonstrated their participation in ageing process. Reciprocally, age-related changes in regulation of receptor responses have been observed in numerous tissues and include modifications of βAR responses. Impaired sympathetic nervous system function has been indeed evoked as at least a partial explanation for several modifications that occur with ageing. This article represents an updated presentation of the current knowledge in the field, summarizing in a systematic way the major findings of research on ageing in several organs and tissues (crime scenes) expressing βARs: heart, vessels, skeletal muscle, respiratory system, brain, immune system, pancreatic islets, liver, kidney and bone

Mechanistic role of β2 adrenergic receptor in glucose homeostasis

In the present article, Wang, Liu, Fu and colleagues report that β2-adrenergic receptor (β2AR) plays a key role in hyperinsulinemia-induced cardiac dysfunction.(1) Overall, the data are very interesting and compelling. However, we noticed that in this paper β2AR-/- mice do not exhibit glucose intolerance; in fact, they seem to have a response to intraperitoneal glucose that is even better than wild-type mice (though a statistical analysis comparing these two groups is not provided). Although surprisingly not reported by the Authors, mounting evidence indicates that the deletion of β2AR has detrimental effects on glucose metabolism.(2-4) Indeed, we have demonstrated that β2AR-/- mice display impaired insulin release and significant glucose intolerance.(2) Muzzin and colleagues found that the ablation of βARs mechanistically underlies impaired glucose homeostasis.(3) Other groups have confirmed these results, also showing that β2AR-/- mice develop diabetic-related microvascular complications (i.e. retinopathy)(4). Nonetheless, the Authors fail to at least discuss previous relevant literature describing the alterations in glucose metabolism observed in β2AR-/- mice and do not accurately circumstantiate their findings. Furthermore, the Authors do not provide any measurement (not in vivo nor in isolated islets) of insulin levels following glucose challenge, showing just baseline serum levels. We believe that for the sake of scientific appropriateness the Readers of Circulation will appreciate a clarification, in particular regarding the fact that pertinent literature in the field has been overlooked

Cardiac Nonmyocyte Cell Functions and Crosstalks in Response to Cardiotoxic Drugs

The discovery of the molecular mechanisms involved in the cardiac responses to anticancer drugs represents the current goal of cardio-oncology research. The oxidative stress has a pivotal role in cardiotoxic responses, affecting the function of all types of cardiac cells, and their functional crosstalks. Generally, cardiomyocytes are the main target of research studies on cardiotoxicity, but recently the contribution of the other nonmyocyte cardiac cells is becoming of growing interest. This review deals with the role of oxidative stress, induced by anticancer drugs, in cardiac nonmyocyte cells (fibroblasts, vascular cells, and immune cells). The alterations of functional interplays among these cardiac cells are discussed, as well. These interesting recent findings increase the knowledge about cardiotoxicity and suggest new molecular targets for both diagnosis and therapy

Physical activity ameliorates cardiovascular health in elderly subjects: the functional role of the Beta adrenergic system.

Aging is a complex process characterized by a gradual decline in organ functional reserves, which eventually reduces the ability to maintain homeostasis. An exquisite feature of elderly subjects, which constitute a growing proportion of the world population, is the high prevalence of cardiovascular disorders, which negatively affect both the quality of life and the life expectancy. It is widely acknowledged that physical activity represents one of the foremost interventions capable in reducing the health burden of cardiovascular disease. Interestingly, the benefits of moderate-intensity physical activity have been established both in young and elderly subjects. Herein we provide a systematic and updated appraisal of the literature exploring the pathophysiological mechanisms evoked by physical activity in the elderly, focusing on the functional role of the β adrenergic system

Insufficient control of blood pressure and incident diabetes

OBJECTIVE: Incidence of type 2 diabetes might be associated with preexisting hypertension. There is no information on whether incident diabetes is predicted by blood pressure control. We evaluated the hazard of diabetes in relation to blood pressure control in treated hypertensive patients. RESEARCH DESIGN AND METHODS: Nondiabetic, otherwise healthy, hypertensive patients (N = 1,754, mean +/- SD age 52 +/- 11 years, 43% women) participated in a network over 3.4 +/- 1 years of follow-up. Blood pressure was considered uncontrolled if systolic was >or=140 mmHg and/or diastolic was >or=90 mmHg at the last outpatient visit. Diabetes was defined according to American Diabetes Association guidelines. RESULTS: Uncontrolled blood pressure despite antihypertensive treatment was found in 712 patients (41%). At baseline, patients with uncontrolledblood pressure were slightly younger than patients with controlled blood pressure (51 +/- 11 vs. 53 +/- 12 years, P < 0.001), with no differences in sex distribution, BMI, duration of hypertension, baseline blood pressure, fasting glucose, serum creatinine and potassium, lipid profile, or prevalence of metabolic syndrome. During follow-up, 109 subjects developed diabetes. Incidence of diabetes was significantly higher in patients with uncontrolled (8%) than in those with controlled blood pressure (4%, odds ratio 2.08, P < 0.0001). In Cox regression analysis controlling for baseline systolic blood pressure and BMI, family history of diabetes, and physical activity, uncontrolled blood pressure doubled the risk of incident diabetes (hazard ratio [HR] 2.10, P < 0.001), independently of significant effects of age (HR 1.02 per year, P = 0.03) and baseline fasting glucose (HR 1.10 per mg/dl, P < 0.001). CONCLUSIONS: In a large sample of treated nondiabetic hypertensive subjects, uncontrolled blood pressure is associated with twofold increased risk of incident diabetes independently of age, BMI, baseline blood pressure, or fasting glucose

Insufficient control of blood pressure and incident diabetes

OBJECTIVE: Incidence of type 2 diabetes might be associated with preexisting hypertension. There is no information on whether incident diabetes is predicted by blood pressure control. We evaluated the hazard of diabetes in relation to blood pressure control in treated hypertensive patients. RESEARCH DESIGN AND METHODS: Nondiabetic, otherwise healthy, hypertensive patients (N = 1,754, mean +/- SD age 52 +/- 11 years, 43% women) participated in a network over 3.4 +/- 1 years of follow-up. Blood pressure was considered uncontrolled if systolic was >or=140 mmHg and/or diastolic was >or=90 mmHg at the last outpatient visit. Diabetes was defined according to American Diabetes Association guidelines. RESULTS: Uncontrolled blood pressure despite antihypertensive treatment was found in 712 patients (41%). At baseline, patients with uncontrolledblood pressure were slightly younger than patients with controlled blood pressure (51 +/- 11 vs. 53 +/- 12 years, P < 0.001), with no differences in sex distribution, BMI, duration of hypertension, baseline blood pressure, fasting glucose, serum creatinine and potassium, lipid profile, or prevalence of metabolic syndrome. During follow-up, 109 subjects developed diabetes. Incidence of diabetes was significantly higher in patients with uncontrolled (8%) than in those with controlled blood pressure (4%, odds ratio 2.08, P < 0.0001). In Cox regression analysis controlling for baseline systolic blood pressure and BMI, family history of diabetes, and physical activity, uncontrolled blood pressure doubled the risk of incident diabetes (hazard ratio [HR] 2.10, P < 0.001), independently of significant effects of age (HR 1.02 per year, P = 0.03) and baseline fasting glucose (HR 1.10 per mg/dl, P < 0.001). CONCLUSIONS: In a large sample of treated nondiabetic hypertensive subjects, uncontrolled blood pressure is associated with twofold increased risk of incident diabetes independently of age, BMI, baseline blood pressure, or fasting glucose

Adrenergic mechanism in the control of endothelial function

There is considerable evidence that many disease are associated with endothelial dysfunction and reduced nitric oxide production such as hypertension, obesity, dyslipidemias, diabetes, heart failure, atherosclerosis. Notably these conditions are also characterized by alteration in the adrenergic tone. Whether these two mechanisms are just epiphenomenal each other or there is a functional link, it is still to be established. A starting ground to establish this issue is that vascular endothelium plays an important role in the function of cardiovascular system and that adrenergic receptors on endothelial cells contribute to the regulation of vasomotor tone. The aim of this excerpt is to review current knowledge on the physiology of endothelial adrenergic receptors to contribute to the basis for newer and better approaches to endothelial dysfunction in the setup of cardiovascular conditions

Preexisting Oral Anticoagulant Therapy Ameliorates Prognosis in Hospitalized COVID-19 Patients

Objective: Altered coagulation parameters in COVID-19 patients is associated with a poor prognosis. We tested whether COVID-19 patients on chronic oral anticoagulants (cOACs) for thromboembolism prophylaxis could receive protection from developing more severe phenotypes of the disease. Approach and Results: We searched the database of the SARS-RAS study (Clinicaltrials.gov: NCT04331574), a cross-sectional observational multicenter nationwide survey in Italy designed by the Italian Society of Hypertension. The database counts 2,377 charts of Italian COVID-19 patients in 26 hospitals. We calculated the Charlson comorbidity index (CCI), which is associated with death in COVID-19 patients. In our population (n = 2,377, age 68.2 ± 0.4 years, CCI: 3.04 ± 0.04), we confirm that CCI is associated with increased mortality [OR: 1.756 (1.628-1.894)], admission to intensive care units [ICU; OR: 1.074 (1.017-1.134)], and combined hard events [CHE; OR: 1.277 (1.215-1.342)]. One hundred twenty-five patients were on cOACs (age: 79.3 ± 0.9 years, CCI: 4.35 ± 0.13); despite the higher CCI, cOACs patients presented with a lower risk of admissions to the ICU [OR 0.469 (0.250-0.880)] but not of death [OR: 1.306 (0.78-2.188)] or CHE [OR: 0.843 (0.541-1.312)]. In multivariable logistic regression, cOACs confirmed their protective effect on ICU admission and CHE. The CCI remains the most important risk factor for ICU admission, death, and CHE. Conclusions: Our data support a mechanism for the continuation of cOAC therapy after hospital admission for those patients who are on chronic treatment. Our preliminary results suggest the prophylactic use of direct cOACs in patients with elevated CCI score at the time of the COVID-19 pandemic even in absence of other risks of thromboembolism

A new synthetic protein, TAT-RH, inhibits tumor growth through the regulation of NFκB activity

Based on its role in angiogenesis and apoptosis, the inhibition of NFkappaB activity is considered an effective treatment for cancer, hampered by the lack of selective and safe inhibitors. We recently demonstrated that the RH domain of GRK5 (GRK5-RH) inhibits NFkappaB, thus we evaluated its effects on cancer growth.The role of GRK5-RH on tumor growth was assessed in a human cancer cell line (KAT-4). RH overexpression was induced by adenovirus mediated gene transfer; alternatively we administered a synthetic protein reproducing the RH domain of GRK5 (TAT-RH), actively transported into the cells.In vitro, adenovirus mediated GRK5-RH overexpression (AdGRK5-NT) in human tumor cells (KAT-4) induces IkappaB accumulation and inhibits NFkappaB transcriptional activity leading to apoptotic events. In BALB/c nude mice harboring KAT-4 induced neoplasias, intra-tumor delivery of AdGRK5-NT reduces in a dose-dependent fashion tumor growth, with the highest doses completely inhibiting it. This phenomenon is paralleled by a decrease of NFkappaB activity, an increase of IkappaB levels and apoptotic events. To move towards a pharmacological setup, we synthesized the TAT-RH protein. In cultured KAT-4 cells, different dosages of TAT-RH reduced cell survival and increased apoptosis. In BALB/c mice, the anti-proliferative effects of TAT-RH appear to be dose-dependent and highest dose completely inhibits tumor growth.Our data suggest that GRK5-RH inhibition of NFkappaB is a novel and effective anti-tumoral strategy and TAT-RH could be an useful tool in the fighting of cancer