scholarly journals AKAP12 Signaling Complex: Impacts of Compartmentalizing cAMP‐Dependent Signaling Pathways in the Heart and Various Signaling Systems

2020 ◽  
Vol 9 (13) ◽  
Author(s):  
Hanan Qasim ◽  
Bradley K. McConnell

Abstract Heart failure is a complex clinical syndrome, represented as an impairment in ventricular filling and myocardial blood ejection. As such, heart failure is one of the leading causes of death in the United States. With a mortality rate of 1 per 8 individuals and a prevalence of 6.2 million Americans, it has been projected that heart failure prevalence will increase by 46% by 2030. Cardiac remodeling (a general determinant of heart failure) is regulated by an extensive network of intertwined intracellular signaling pathways. The ability of signalosomes (molecular signaling complexes) to compartmentalize several cellular pathways has been recently established. These signalosome signaling complexes provide an additional level of specificity to general signaling pathways by regulating the association of upstream signals with downstream effector molecules. In cardiac myocytes, the AKAP12 (A‐kinase anchoring protein 12) scaffolds a large signalosome that orchestrates spatiotemporal signaling through stabilizing pools of phosphatases and kinases. Predominantly upon β‐AR (β 2 ‐adrenergic‐receptor) stimulation, the AKAP12 signalosome is recruited near the plasma membrane and binds tightly to β‐AR. Thus, one major function of AKAP12 is compartmentalizing PKA (protein kinase A) signaling near the plasma membrane. In addition, it is involved in regulating desensitization, downregulation, and recycling of β‐AR. In this review, the critical roles of AKAP12 as a scaffold protein in mediating signaling downstream GPCRs (G protein–coupled receptor) are discussed with an emphasis on its reported and potential roles in cardiovascular disease initiation and progression.

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ayesha Azmeen ◽  
Naga Vaishnavi Gadela ◽  
Vergara Cunegundo

Introduction: Heart failure(HF) is a clinical syndrome that is widely prevalent affecting approximately 6.5 million people in the United States. It accounts for the ever-rising health care costs in the US due to recurrent hospitalizations. Despite advancements in medical management, the mortality and the rate of hospitalizations continues to be high with geographic variations and racial disparities. Through this descriptive study, we sought to analyze the health disparities among Hispanic, African American (AA) and Caucasian population in a single-center. Methods: We identified a total of 178 patients with HF with reduced ejection fraction from our outpatient clinic by utilizing the ICD-10 codes. Patients with ejection fraction >50% have been excluded. A retrospective chart review of their ethnic background, medications, and number of heart failure exacerbations per year has been performed. Results: 178 patients (mean age 62 years, 35.56% of females) including Hispanics (n=102), AA(n=44), and Caucasians (n=32) were included in the study. Although all patients were started on Beta-blockers, only 76.4% and 37.2% of Hispanics were started on ACEi/ARBs and spironolactone respectively. Similarly, 72.7% and 45.4% of AA were started on ACEi/ARBs and spironolactone respectively. This is in contrast to Caucasians population, where a majority of patients were on started on GDMT; 90% and 75% were started on ACEi/ARBs and spironolactone respectively. This was also reflected by the number of admissions due to HF exacerbations which ranged from 2-4/year for Hispanics and AA populations and 0-1/year for Caucasians. Conclusions: GDMT for HF is known to reduce heart failure exacerbations, mortality and the ever rising cost of the healthcare system. We have observed that despite recommendations to initiate GDMT in all patients with HF with reduced ejection fraction, racial disparities exist. Physicians should be mindful of initiating GDMT in all patients.


Nutrients ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 1120 ◽  
Author(s):  
Levi Evans ◽  
Bradley Ferguson

Approximately 5.7 million U.S. adults have been diagnosed with heart failure (HF). More concerning is that one in nine U.S. deaths included HF as a contributing cause. Current HF drugs (e.g., β-blockers, ACEi) target intracellular signaling cascades downstream of cell surface receptors to prevent cardiac pump dysfunction. However, these drugs fail to target other redundant intracellular signaling pathways and, therefore, limit drug efficacy. As such, it has been postulated that compounds designed to target shared downstream mediators of these signaling pathways would be more efficacious for the treatment of HF. Histone deacetylation has been linked as a key pathogenetic element for the development of HF. Lysine residues undergo diverse and reversible post-translational modifications that include acetylation and have historically been studied as epigenetic modifiers of histone tails within chromatin that provide an important mechanism for regulating gene expression. Of recent, bioactive compounds within our diet have been linked to the regulation of gene expression, in part, through regulation of the epi-genome. It has been reported that food bioactives regulate histone acetylation via direct regulation of writer (histone acetyl transferases, HATs) and eraser (histone deacetylases, HDACs) proteins. Therefore, bioactive food compounds offer unique therapeutic strategies as epigenetic modifiers of heart failure. This review will highlight food bio-actives as modifiers of histone deacetylase activity in the heart.


2018 ◽  
Vol 25 (22) ◽  
pp. 2608-2623 ◽  
Author(s):  
Carolina Torres ◽  
Andrew M. Diaz ◽  
Daniel R. Principe ◽  
Paul J. Grippo

Cancer is a major public health problem worldwide and is the second leading cause of death in the United States. Although cancer death rate has dropped by 23% since 1991, there are certain types of cancer for which death rates are still increasing, such as pancreatic cancer. There is an urgent need to find new therapies that could help improve this dreadful outcome. In this regard, the role of nutrition in health and disease has attracted much attention. Several dietary components are involved in metabolic, physiologic and cell signaling affecting tumor growth and progression. Although lipids, and more specifically polyunsaturated fatty acids, have been traditionally studied due to their health effects in cardiovascular disease, it is now clear that they can impact an extensive array of cellular processes that influence a wide range of diseases such as type II diabetes, inflammatory disorders and cancer. These biological activities may be grouped as regulation of: (1) membrane structure and function, (2) intracellular signaling pathways, (3) transcription factor activity, (4) gene expression, and (5) production of bioactive lipid mediators. The aim of this review is to assimilate the current state of knowledge about these potential mechanism(s) of action and signaling pathways modulated by polyunsaturated fatty acids in pancreatic cancer.


2014 ◽  
Vol 25 (2) ◽  
pp. 151-162
Author(s):  
Denise Buonocore ◽  
Elizabeth Wallace

Heart failure (HF) is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. More than 5.1 million people are living with HF in the United States today. This number will continue to rise with the increase in the aging population. With so many people living with HF, nurses need to be well versed on how best to care for them. The 2013 American College of Cardiology Foundation/American Heart Association guideline for the management of HF is a comprehensive guide for all clinicians caring for patients with HF. The updated guideline was developed to assist providers in decision making in the diagnosis and treatment of HF. The goals of the writing committee were to improve quality of care for patients with HF, optimize their outcomes, and improve the efficient use of various resources in the treatment of patients with HF.


2010 ◽  
Vol 17 (3) ◽  
pp. R195-R212 ◽  
Author(s):  
Fazlul H Sarkar ◽  
Yiwei Li ◽  
Zhiwei Wang ◽  
Dejuan Kong

Among many endocrine-related cancers, prostate cancer (PCa) is the most frequent male malignancy, and it is the second most common cause of cancer-related death in men in the United States. Therefore, this review focuses on summarizing the knowledge of molecular signaling pathways in PCa because, in order to better design new preventive strategies for the fight against PCa, documentation of the knowledge on the pathogenesis of PCa at the molecular level is very important. Cancer cells are known to have alterations in multiple cellular signaling pathways; indeed, the development and the progression of PCa are known to be caused by the deregulation of several selective signaling pathways such as the androgen receptor, Akt, nuclear factor-κB, Wnt, Hedgehog, and Notch. Therefore, strategies targeting these important pathways and their upstream and downstream signaling could be promising for the prevention of PCa progression. In this review, we summarize the current knowledge regarding the alterations in cell signaling pathways during the development and progression of PCa, and document compelling evidence showing that these are the targets of several natural agents against PCa progression and its metastases.


el–Hayah ◽  
2014 ◽  
Vol 4 (2) ◽  
pp. 81 ◽  
Author(s):  
Lailia Nur Rachma

<em>Heart failure is a clinical syndrome characterized by abnormalities in the structure or function of the heart, resulting in inability of heart to pump blood to meet the metabolic needs of the body tissue. Heart failure is characterized by clinical manifestations such as circulation congestion, tightness, fatigue, and weakness. Heart failure is a major problem in industrial and developing Country. Currently, the incidence and prevalence of heart failure tends to increase, it is also accompanied by an increase in mortality of heart failure cases. In the United States, 1 million patients hospitalized due to heart failure cases, which contribute to 50,000 deaths each year. While the number of visits to the hospital due to heart failure estimated at 6.5 million. Heart failure prognosis is generally poor despite the patients accepted adequate therapy. From the data obtained, only about 35% of male patients and 50% female patients who survived after the onset of acute heart failure. Generaly, the data obtained high mortality are occurs in patients with grade IV (presence of symptoms at rest) is about 30-70%, grade III (presence of symptoms with mild activity) 10-20%, class II (presence of symptoms when the activity being 5-10 %). Higher mortality was found in older patients, men, patients with reduced ejection fraction, and in patients with coronary disease. Once someone is suffering from heart failure, then he shall bear the very high cost. In America, the cost of issued for heart failure therapy between 15-40 trillion US$. In this review, we will discuss about pathomechanism of heart failure. So it is expected to be a reference to the diagnosis of patients with heart failure, which is expected to be recognized early on that could ultimately improve the quality of heart failure patient life, and reduce the number of mortality due to heart failure</em>


Author(s):  
А.В. Муравьев ◽  
П.В. Михайлов ◽  
И.А. Тихомирова ◽  
Н. Антонова ◽  
А.А. Муравьев

Введение. Эритроциты — высокоспециализированные клетки, основной функцией которых является транспорт кислорода. Они лишены ядра и митохондрий, однако сохранили многие элементы молекулярных сигнальных путей. При выполнении транспортной функции эритроциты изменяют свои механические свойства и в том числе деформируются и объединяются в комплексы — агрегаты. Имеется ряд свидетельств того, что изменение механических свойств эритроцитов происходит под влиянием сигнальных молекул, к которым относятся и газовые медиаторы или газотрансмиттеры (ГТ). Это оксид азота, монооксид углерода и сульфид водорода. Цель исследования: изучение микрореологических ответов человеческих эритроцитов на действие ряда доноров газотрансмиттеров — оксида азота и сульфида водорода. Материалы и методы. После инкубирования эритроцитов с донорами оксида азота (спермином и нитропруссидом натрия) и донором сульфида водорода (гидросульфидом натрия) регистрировали деформируемость эритроцитов, их агрегацию и вязкость суспензий клеток (показатель гематокрита — 40%, вязкость суспензионной среды — 1,30 мПа × с; раствор Рингера и декстран‑200). Для уточнения механизмов действия ГТ на микрореологические свойства эритроцитов их инкубировали с ацетилхолином, серотонином и форсколином. Результаты. Установлено, что под влиянием ГТ происходят заметные изменения микромеханических свойств эритроцитов, которые статистически значимо изменялись под влиянием доноров оксида азота. Более существенные сдвиги микрореологии клеток, особенно их агрегацию, вызывал нитропруссид натрия. Гидросульфид натрия умеренно, но статистически значимо повышал деформируемость эритроцитов и заметно снижал их агрегацию, однако его эффекты уступали действию нитропруссида натрия. Заключение. На основании полученных данных и их анализа можно полагать, что внутриклеточными сигнальными путями для исследованных ГТ в эритроцитах при изменении их микромеханического состояния могут быть как ферменты гуанилатциклаза и аденилатциклаза, так и ионные каналы мембраны клетки. Introduction. Erythrocytes are highly specialized cells; oxygen transport is their main function. They have no nucleus and mitochondria, but they saved many elements of molecular signaling pathways. When erythrocytes performed the transport function they change their mechanical properties, deformed and combined into complexes — aggregates. There are some data that erythrocytes change their mechanical properties under the influence of signaling molecules such as gas mediators or gasotransmitters (GTs) — nitric oxide (NO), carbon monoxide and hydrogen sulfide. Aim: to study the microrheological responses of erythrocytes on the action of number GTs-donors — nitric oxide and hydrogen sulfide. Materials and methods. After erythrocytes incubation with NO-donors (spermine and sodium nitroprusside) and donor of hydrogen sulfide (sodium hydrosulfide) we registered erythrocytes deformability, their aggregation and viscosity of cell suspensions (hematocrit — 40%, viscosity of suspension medium — 1.30 mPa × s; Ringer’s solution and dextran‑200). To clarify the mechanisms of GTs action on microrheological properties of erythrocytes they were incubated with acetylcholine, serotonin and forskolin. Results. GTs noticeably changed erythrocytes micromechanical properties. Sodium nitroprusside caused significant shifts of erythrocytes microrheology, especially of erythrocytes aggregation. Sodium hydrosulfide moderately but statistically significant increased erythrocytes deformability and markedly reduced erythrocytes aggregation, but its effects were inferior to that of sodium nitroprusside. Conclusion. The study results suggest that guanylate cyclase and adenylate cyclase, as well as the ion channels of the cell membrane can be the intracellular signaling pathways in erythrocytes for investigated GTs.


2017 ◽  
Vol 95 (3) ◽  
pp. 253-259 ◽  
Author(s):  
Amanda M. Marsh ◽  
Austin Huy Nguyen ◽  
Taylor M. Parker ◽  
Devendra K. Agrawal

Heart failure (HF) is a clinical syndrome that represents the end stage of heart disease and remains the leading cause of morbidity and mortality worldwide. As heart failure mortality rates remain elevated, additional biomarkers that facilitate early detection or risk stratification in HF is of particularly great interest. High mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE) cause the activation of intracellular signaling, gene expression, and production of inflammatory cytokines and have been linked to many inflammatory disease states such as diabetes mellitus and atherosclerosis. Few studies have investigated their role in the pathophysiology of HF and any significant correlation remains uncertain. Review of the available literature discussing HMGB1 and RAGE clinical values as independent prognostic variables in HF resulted in the inclusion of 11 studies, which enrolled a total of 2025 heart failure patients. Overall, the data suggests a statistically significant positive correlation between RAGE and HF, with increasing RAGE levels associated with increasing New York Heart Association (NYHA) functional class of heart failure. HMGB1 correlations were not as extensively studied, but there is evidence that both HMGB1 and RAGE have a definite potential as biomarkers for the prognosis and risk stratification of HF patients.


2016 ◽  
Vol 39 (1) ◽  
pp. 371-384 ◽  
Author(s):  
Paula F. Martinez ◽  
Camila Bonomo ◽  
Daniele M. Guizoni ◽  
Silvio A. Oliveira Junior ◽  
Ricardo L. Damatto ◽  
...  

Background/Aims: Although increased oxidative stress plays a role in heart failure (HF)-induced skeletal myopathy, signaling pathways involved in muscle changes and the role of antioxidant agents have been poorly addressed. We evaluated the effects of N-acetylcysteine (NAC) on intracellular signaling pathways potentially modulated by oxidative stress in soleus muscle from HF rats. Methods and Results: Four months after surgery, rats were assigned to Sham, myocardial infarction (MI)-C (without treatment), and MI-NAC (treated with N-acetylcysteine) groups. Two months later, echocardiogram showed left ventricular dysfunction in MI-C; NAC attenuated diastolic dysfunction. Oxidative stress was evaluated in serum and soleus muscle; malondialdehyde was higher in MI-C than Sham and did not differ between MI-C and MI-NAC. Oxidized glutathione concentration in soleus muscle was similar in Sham and MI-C, and lower in MI-NAC than MI-C (Sham 0.168 ± 0.056; MI-C 0.223 ± 0.073; MI-NAC 0.136 ± 0.023 nmol/mg tissue; p = 0.014). Western blot showed increased p-JNK and decreased p38, ERK1/2, and p-ERK1/2 in infarcted rats. NAC restored ERK1/2. NF-κB p65 subunit was reduced; p-Ser276 in p65 and IκB was increased; and p-Ser536 unchanged in MI-C compared to Sham. NAC did not modify NF-κB p65 subunit, but decreased p-Ser276 and p-Ser536. Conclusion: N-acetylcysteine modulates MAPK and NF-κB signaling pathways in soleus muscle of HF rats.


Sign in / Sign up

Export Citation Format

Share Document