Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction

Unsöld, Bernhard; Kaul, Axel; Sbroggiò, Mauro; Schubert, Carola; Regitz‐Zagrosek, Vera; Brancaccio, Mara; Damilano, Federico; Hirsch, Emilio; Bilsen, Marc van; Munts, Chantal; Sipido, Karin R.; Bito, Virginie; Detre, Elke; Wagner, Nana-Maria; Schäfer, Katrin; Seidler, Tim; Vogt, Johannes; Neef, Stefan; Bleckmann, Annalen; Maier, Lars S.; Balligand, Jean‐Luc; Bouzin, Caroline; Ventura‐Clapier, Renée; Garnier, Anne; Eschenhagen, Thomas; El‐Armouche, Ali; Knöll, Ralph; Tarone, Guido; Hasenfuß, Gerd

doi:10.1093/cvr/cvt235

Cited by 44 publications

(34 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cardiac rupture and negative remodeling following MI worsen morbidity and mortality due to cardiomyocyte necrosis, apoptosis and myocardial fibrosis [33,34]. It has been purported that ER stress may play a crucial role in the pathogenesis of these detrimental sequelae, with the GRP78-PERK-CHOP cross-talk at its center [35–37].…”

Section: Discussionmentioning

confidence: 99%

Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis

Luo

Kim

Chen

et al. 2015

Chemico-Biological Interactions

View full text Add to dashboard Cite

Endoplasmic reticulum (ER) stress is implicated in the pathophysiology of various cardiovascular diseases, but the role of ER stress in cardiac rupture and/or remodeling after myocardial infarction (MI) is still unclear. Here we investigated whether ER stress plays a major role for these processes in mice. We ligated the left coronary artery (LCA) without reperfusion in mice and administered either NaCl or 4-phenylbutyric acid (4-PBA, 20 mg/kg/d) intraperitoneally for 4 weeks. Cardiac rupture rates during the first week of MI were 37.5% and 18.2% in the control and 4-PBA groups, respectively. The extent of ventricular aneurysm and fibrosis was less, and the cardiac function better, in the 4-PBA group compared with the control group. The protein levels of ER stress markers in the heart tissues of the control group remained elevated during the entire 4-week period after MI, while pro-apoptotic proteins mainly increased in the early phase, and the pro-fibrotic proteins markedly increased in the late phase post MI; 4-PBA decreased all of these protein levels. In the primary cultured neonatal rat cardiomyocytes or fibroblasts, hypoxia (3% O 2 ) increased the number of apoptotic cardiomyocytes and promoted the proliferation and migration of fibroblasts, all of which were attenuated by 4-PBA (0.5 mM). These findings indicate that MI induces ER stress and provokes cardiac apoptosis and fibrosis, culminating in cardiac rupture and remodeling,

show abstract

Section: Discussionmentioning

confidence: 99%

Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis

Luo

Kim

Chen

et al. 2015

Chemico-Biological Interactions

View full text Add to dashboard Cite

show abstract

“…Several factors may cooperate to induce cardiac rupture in vulnerable individuals, including a large transmural infarction, an accentuated (or prolonged) inflammatory reaction, and an impaired (or delayed) reparative response. Extensive evidence suggests that excessive inflammation is associated with cardiac rupture (63,158) and that targeted interventions inhibiting proinflammatory signaling may protect from this catastrophic complication (372). Moreover, activation of matrix-degrading proteases is also implicated in the pathogenesis of cardiac rupture following infarction (153,386).…”

Section: Pathophysiology Of Complications Associated With Myocardial mentioning

confidence: 99%

Pathophysiology of Myocardial Infarction

Frangogiannis

2015

Comprehensive Physiology

504

391

View full text Add to dashboard Cite

Myocardial infarction is defined as sudden ischemic death of myocardial tissue. In the clinical context, myocardial infarction is usually due to thrombotic occlusion of a coronary vessel caused by rupture of a vulnerable plaque. Ischemia induces profound metabolic and ionic perturbations in the affected myocardium and causes rapid depression of systolic function. Prolonged myocardial ischemia activates a "wavefront" of cardiomyocyte death that extends from the subendocardium to the subepicardium. Mitochondrial alterations are prominently involved in apoptosis and necrosis of cardiomyocytes in the infarcted heart. The adult mammalian heart has negligible regenerative capacity, thus the infarcted myocardium heals through formation of a scar. Infarct healing is dependent on an inflammatory cascade, triggered by alarmins released by dying cells. Clearance of dead cells and matrix debris by infiltrating phagocytes activates anti-inflammatory pathways leading to suppression of cytokine and chemokine signaling. Activation of the renin-angiotensin-aldosterone system and release of transforming growth factor-β induce conversion of fibroblasts into myofibroblasts, promoting deposition of extracellular matrix proteins. Infarct healing is intertwined with geometric remodeling of the chamber, characterized by dilation, hypertrophy of viable segments, and progressive dysfunction. This review manuscript describes the molecular signals and cellular effectors implicated in injury, repair, and remodeling of the infarcted heart, the mechanistic basis of the most common complications associated with myocardial infarction, and the pathophysiologic effects of established treatment strategies. Moreover, we discuss the implications of pathophysiological insights in design and implementation of new promising therapeutic approaches for patients with myocardial infarction.

show abstract

“…2 and 16). In human heart failure patients and animal models of hypertrophy melusin levels are downregulated (81, 138, 148), and overexpression of melusin in mice is cardioprotective (699). Due to melusin’s cardioprotective effects, it is being pursued as a possible therapeutic for heart failure.…”

Section: The Costamere: Protects Against Mechanical Stress and Is An mentioning

confidence: 99%

Overview of the Muscle Cytoskeleton

Henderson

Gomez

Novak

et al. 2017

Comprehensive Physiology

220

193

View full text Add to dashboard Cite

Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease.

show abstract

Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction

Cited by 44 publications

References 45 publications

Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis

Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis

Pathophysiology of Myocardial Infarction

Overview of the Muscle Cytoskeleton

Contact Info

Product

Resources

About