Full Expression of Cardiomyopathy Is Partly Dependent on B‐Cells: A Pathway That Involves Cytokine Activation, Immunoglobulin Deposition, and Activation of Apoptosis

Cordero‐Reyes, Andrea M.; Youker, Keith A.; Trevino, Alejandro R.; Celis, René; Hamilton, Dale J.; Flores‐Arredondo, Jose H.; Orrego, Carlos M.; Bhimaraj, Arvind; Estep, Jerry D.; Torre‐Amione, Guillermo

doi:10.1161/jaha.115.002484

Cited by 75 publications

(83 citation statements)

References 30 publications

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“…For instance, the pathogenesis of ANG II-induced dilated cardiomyopathy was reported to depend on the T cell Th2 phenotype (816) and to involve the Th2 polarizing cytokine IL-4 (815). Others recently showed that B cells have a contributory role in an ANG II-induced model of heart failure (186).…”

Section: Ang II In Cardiac Hypertrophymentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

773

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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Section: Ang II In Cardiac Hypertrophymentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

773

780

View full text Add to dashboard Cite

show abstract

“…By contrast, M2-like macrophages (CD206 + F4/80 + CD11b + ) exert profound functions on tissue repair in heart depending on IL4 secretion (156). Recent studies implicate TNFβ producing B cells as a major contributor to myocardial fibrosis (153, 157). Antigen and cytokine stimulation are known to differentiate naive T cells into distinct T cell subpopulations that include T helper cells and CD4 + CD25 + FOXP3 + T Reg cells (158).…”

Section: Inflammation Innate and Adaptive Immune Responsesmentioning

confidence: 99%

Diabetic Cardiomyopathy: An Immunometabolic Perspective

et al. 2017

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The heart possesses a remarkable inherent capability to adapt itself to a wide array of genetic and extrinsic factors to maintain contractile function. Failure to sustain its compensatory responses results in cardiac dysfunction, leading to cardiomyopathy. Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction in the absence of hypertension and coronary artery disease. Changes in substrate metabolism, oxidative stress, endoplasmic reticulum stress, formation of extracellular matrix proteins, and advanced glycation end products constitute the early stage in DCM. These early events are followed by steatosis (accumulation of lipid droplets) in cardiomyocytes, which is followed by apoptosis, changes in immune responses with a consequent increase in fibrosis, remodeling of cardiomyocytes, and the resultant decrease in cardiac function. The heart is an omnivore, metabolically flexible, and consumes the highest amount of ATP in the body. Altered myocardial substrate and energy metabolism initiate the development of DCM. Diabetic hearts shift away from the utilization of glucose, rely almost completely on fatty acids (FAs) as the energy source, and become metabolically inflexible. Oxidation of FAs is metabolically inefficient as it consumes more energy. In addition to metabolic inflexibility and energy inefficiency, the diabetic heart suffers from impaired calcium handling with consequent alteration of relaxation–contraction dynamics leading to diastolic and systolic dysfunction. Sarcoplasmic reticulum (SR) plays a key role in excitation–contraction coupling as Ca2+ is transported into the SR by the SERCA2a (sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a) during cardiac relaxation. Diabetic cardiomyocytes display decreased SERCA2a activity and leaky Ca2+ release channel resulting in reduced SR calcium load. The diabetic heart also suffers from marked downregulation of novel cardioprotective microRNAs (miRNAs) discovered recently. Since immune responses and substrate energy metabolism are critically altered in diabetes, the present review will focus on immunometabolism and miRNAs.

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“…Heart failure, hypertrophy, myocardial fibrosis, myocardial infarction, ischemia-reperfusion (43,44) TGF-β/smad signaling glg1, pdpk1(s117), jun(s63), lemd3, fbn2, men1, zeb1, aspn, eng, snx6, zfyve9, cav3, sptbn1, bcl9l, strap, cav2,* ppm1a, htra1…”

Section: Pathwaymentioning

confidence: 99%

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

Kuzmanov

Guo

Buchsbaum

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Phospholamban (PLN) plays a central role in Ca2+ homeostasis in cardiac myocytes through regulation of the sarco(endo)plasmic reticulum Ca 2+ -ATPase 2A (SERCA2A) Ca 2+ pump. An inherited mutation converting arginine residue 9 in PLN to cysteine (R9C) results in dilated cardiomyopathy (DCM) in humans and transgenic mice, but the downstream signaling defects leading to decompensation and heart failure are poorly understood. Here we used precision mass spectrometry to study the global phosphorylation dynamics of 1,887 cardiac phosphoproteins in early affected heart tissue in a transgenic R9C mouse model of DCM compared with wild-type littermates. Dysregulated phosphorylation sites were quantified after affinity capture and identification of 3,908 phosphopeptides from fractionated whole-heart homogenates. Global statistical enrichment analysis of the differential phosphoprotein patterns revealed selective perturbation of signaling pathways regulating cardiovascular activity in early stages of DCM. Strikingly, dysregulated signaling through the Notch-1 receptor, recently linked to cardiomyogenesis and embryonic cardiac stem cell development and differentiation but never directly implicated in DCM before, was a prominently perturbed pathway. We verified alterations in Notch-1 downstream components in early symptomatic R9C transgenic mouse cardiomyocytes compared with wild type by immunoblot analysis and confocal immunofluorescence microscopy. These data reveal unexpected connections between stress-regulated cell signaling networks, specific protein kinases, and downstream effectors essential for proper cardiac function.phospholamban | proteomic | bioinformatics | heart disease | signaling C ardiovascular diseases (CVDs) leading to systolic/diastolic heart failure (HF), such as hypertensive/diabetic heart disease, stroke, and vascular atherosclerosis, are leading causes of death in the developed world (1). Many CVDs are associated with genetic predispositions. For example, in humans, the arginine to cysteine (R9C) substitution in phospholamban (PLN) has been shown to result in dilated cardiomyopathy (DCM) presenting in adolescence, leading to rapid deterioration of heart function and premature death (2). However, the etiology and molecular mechanisms of progression of DCM and other CVDs leading to HF are complex and still poorly understood, further complicating clinical assessment and management. From a biological and clinical perspective, the identification and characterization of clinically relevant, potentially druggable, pathways driving the maladaptive response in affected heart tissue are key challenges to improved diagnostic and therapeutic tools for earlier detection and preventative treatment of both inherited and chronic CVDs.Cardiac muscle contraction is controlled by Ca 2+ flux and signaling relays, which are perturbed in HF. Internal stores of Ca 2+ required for the proper functioning of cardiomyocytes (CMs) are normally maintained through the function of the sarco(endo)plasmic reticulum Ca 2+ -ATPase 2 ...

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Full Expression of Cardiomyopathy Is Partly Dependent on B‐Cells: A Pathway That Involves Cytokine Activation, Immunoglobulin Deposition, and Activation of Apoptosis

Cited by 75 publications

References 30 publications

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Diabetic Cardiomyopathy: An Immunometabolic Perspective

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

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