Current Opinion in Physiology最新文献

Cardiotoxicity, or the development of unwarranted cardiovascular side-effects of oncologic therapies, can involve all aspects of cardiovascular disease. The development of cardiac fibrosis is a dreaded complication that leads to cardiac mechanical dysfunction, tachyarrhythmias, and an increase in cardiovascular mortality. This review details established and putative mechanisms, leading to fibroblast activation, myofibroblast transdifferentiation, and the development of replacement or interstitial cardiac fibrosis as a consequence of cancer treatments. Clinical and imaging strategies for cardiac fibrosis assessment as well as emerging antifibrotic therapeutics will also be addressed.

Lysosomes are subjected to physiological and pathophysiological insults over the course of their life cycle and are accordingly repaired or recycled. Lysophagy, the selective degradation of lysosomes via autophagy, occurs upon unrepairable lysosomal-membrane rupture; galectins bind to glycosylated macromolecules in the lysosome lumen, orchestrating a series of cellular responses to promote autophagic recycling of damaged lysosomes and transcriptional upregulation of lysosomal genes. Damaged lysosomes are ubiquitylated, resulting in the recruitment of ubiquitin-binding autophagy receptors, which promote assembly of an autophagosome around damaged lysosomes for delivery to healthy lysosomes for degradation. Here, we review the current state of our understanding of mechanisms used to mark and eliminate damaged lysosomes, and discuss the complexities of galectin function and ubiquitin-chain linkage types. Finally, we discuss the limitations of available data and challenges with the goal of understanding the mechanistic basis of key steps in lysophagic flux.

Autophagy is a highly conserved and critical recycling and degradation pathway that involves the selective engulfment of cytoplasmic organelles and proteins into double-membrane vesicles termed autophagosomes that subsequently fuse with lysosomes for degradation. In addition to its established role in protein degradation, there is a growing body of evidence that in response to specific environmental cues, the autophagy machinery promotes unconventional secretion of leaderless proteins via diverse mechanisms, collectively termed ‘secretory autophagy’. In this review, we describe recent findings highlighting these noncanonical functions of the autophagy machinery in specifying vesicular cargo loading for secretion and discuss how secretory autophagy is regulated during a wide range of cellular stresses, including inflammation, starvation, and lysosomal damage.

Remodeling of the myocardium results in changes in the molecular, cellular, and microstructural properties of the heart. Traditionally, these changes have been characterized using microscopy of tissue specimens taken from the heart. However, recent advances in biomedical imaging now make it possible to characterize many of these processes noninvasively. In this review, we focus on key principles and recent advances in molecular, cellular, and microstructural imaging of the heart after ischemic injury. Techniques to image cardiomyocyte death, inflammation, fibrosis, and microstructural remodeling of the heart are highlighted.

The mitochondria play an important role in the activation of the innate immune system. This organelle modulates the metabolic reprogramming of the immune cell into proinflammatory or anti-inflammatory subtypes, which typically utilize very different metabolic pathways to fulfill their functions. It also acts as a signaling platform to activate immune routes in both immune and nonimmune cells, as it can generate agonists for inflammatory pathways, including toll-like receptors, inflammasomes, or the cyclic GMP–AMP synthase–stimulator of interferon genes pathway, which lead to the generation of proinflammatory cytokines and antiviral molecules such as type-I interferons. These novel functions of the mitochondria are important in the fight against pathogens, but also contribute to human disease when dysregulated. This review describes recent findings in this field and highlights the role of mitochondrial nucleic acids in the regulation of innate immune signaling pathways.

Cardiac fibroblasts (CFs) exist in a variety of states that contribute to either conserved or uncontrolled extracellular matrix (ECM) deposition. In healthy hearts, fibroblasts favor the homeostatic or quiescent state in which they work to maintain the ECM at a baseline level of activity. Acute or chronic injury in the form of myocardial infarction, hypertension, and heart failure induce CF activation via increased pro-oxidant, proinflammatory, and profibrotic stimuli secondary to hypoxia, cardiomyocyte cell death, or hemodynamic stress. In addition to the well-described signaling molecules that induce CF activation (e.g. transforming growth factor beta 1, angiotensin II, and reactive oxygen species), there are emerging concepts that describe mechanisms that regulate more nuanced transition between activation states. This review will discuss recent descriptions of heterogeneous populations of resident cardiac fibroblasts, states of fibroblast activation, and the roles for mitochondrial and chromatin accessibility in mediating transition to and persistence of the activated state.

Most cellular protein synthesis, including synthesis of membrane-targeted and secreted proteins, which are critical for cellular and organ crosstalk, takes place at the endoplasmic reticulum (ER), placing the ER at the nexus of cellular signaling, growth, metabolism, and stress sensing. Ample evidence has established the dysregulation of protein homeostasis and the ER unfolded protein response (UPR) in cardiovascular disease. However, the mechanisms of stress sensing and signaling in the ER are incompletely defined. Recent studies have defined notable functions for the inositol-requiring kinase 1 (IRE1)/X-box- binding protein-1 (XBP1) branch of the UPR in regulation of cardiac function. This review highlights the mechanisms underlying IRE1 activation and the IRE1 interactome, which reveals unexpected functions for the UPR and summarizes our current understanding of the functions of IRE1 in cardiovascular disease.

Post-transcriptional modifications encompass a large group of RNA alterations that control gene expression. Methylation of the N⁶-adenosine (m⁶A) of mRNA is a prevalent modification that alters the life cycle of transcripts. The roles that m⁶A play in regulating cardiac homeostasis and injury response are an active area of investigation, but it is clear that this chemical modification is a critical controller of fibroblast-to-myofibroblast transition, cardiomyocyte hypertrophy and division, and the structure and function of the extracellular matrix. Here, we discuss the latest findings of m⁶A in cardiac muscle and matrix.

Cardiac fibroblasts play critical roles in the maintenance of cardiac structure and the response to cardiac insult. Extracellular matrix deposition by activated resident cardiac fibroblasts, called myofibroblasts, is an essential wound healing response. However, persistent fibroblast activation contributes to pathological fibrosis and cardiac chamber stiffening, which can cause diastolic dysfunction, heart failure, and initiate lethal arrhythmias. The dynamic and phenotypically plastic nature of cardiac fibroblasts is governed in part by the transcriptional regulation of genes encoding extracellular matrix molecules. Understanding how fibroblasts integrate various biomechanical cues into a precise transcriptional response may uncover therapeutic strategies to prevent fibrosis. Here, we provide an overview of the recent literature on transcriptional control of cardiac fibroblast plasticity and fibrosis, with a focus on canonical and noncanonical transforming growth factor beta signaling, biomechanical regulation of Hippo/yes-associated protein and Rho/myocardin-related transcription factor signaling, and metabolic and epigenetic control of fibroblast activation.

Interstitial cardiac fibrosis arises due to deposition and accumulation of extracellular matrix (ECM) and occurs in hearts subject to increases in mechanical load. Cardiac fibroblasts sense changes in mechanical load through several mechanosensors including integrin ECM receptors and stretch activated ion channels, which signal to induce ECM protein production through various pathways. Over time, processes intrinsic to fibroblasts and to the ECM occur to progress and sustain fibrosis through reciprocal, positive feedback loops. Changes in ECM include nascent collagen production, changes in ECM composition, and differential modification of collagen in fibers. Persistently fibrotic ECM contributes to a stiffer myocardium which can lead to the development of cardiomyopathies and heart failure.