Heart Failure and Mitochondrial Dysfunction

Knowlton, Anne A; Chen, Le; Malik, Zulfiqar Ali

doi:10.1097/01.fjc.0000432861.55968.a6

Cited by 77 publications

(39 citation statements)

References 132 publications

(178 reference statements)

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“…Extracellular histones function as endogenous DAMPs that might interact with TLR2 and TLR4 on various cell types, including cardiomyocytes to reduce mitochondrial membrane potential and ATP levels. These activities cause cell damage, the dysfunction of organs including the heart, and lethality [ 82 – 84 ]. Extracellular histones appear to arise in a complement (C5a)-dependent fashion related to neutrophil activation that results in neutrophil extracellular traps (NETs) [ 85 ].…”

Section: Reviewmentioning

confidence: 99%

Sepsis-induced myocardial dysfunction: pathophysiology and management

et al. 2016

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Sepsis is aggravated by an inappropriate immune response to invading microorganisms, which occasionally leads to multiple organ failure. Several lines of evidence suggest that the ventricular myocardium is depressed during sepsis with features of diastolic dysfunction. Potential candidates responsible for septic cardiomyopathy include pathogen-associated molecular patterns (PAMPs), cytokines, and nitric oxide. Extracellular histones and high-mobility group box 1 that function as endogenous damage-associated molecular patterns (DAMPs) also contribute to the myocardial dysfunction associated with sepsis. If untreated, persistent shock causes cellular injury and the liberation of further DAMPs. Like PAMPs, DAMPs have the potential to activate inflammation, creating a vicious circle. Early infection control with adequate antibiotic care is important during septic shock to decrease PAMPs arising from invasive microorganisms. Early aggressive fluid resuscitation as well as the administration of vasopressors and inotropes is also important to reduce DAMPs generated by damaged cells although excessive volume loading, and prolonged administration of catecholamines might be harmful. This review delineates some features of septic myocardial dysfunction, assesses its most common underlying mechanisms, and briefly outlines current therapeutic strategies and potential future approaches.

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Section: Reviewmentioning

confidence: 99%

Sepsis-induced myocardial dysfunction: pathophysiology and management

et al. 2016

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“…Mfn1/2 are found on the outer mitochondrial membrane, where they can make hetero- or homo-dimeric interactions with neighboring mitochondria. Mfn1/2, unlike Opa1, are increased in some forms of heart failure [163]. Mfn1/Mfn2 plays a large role in autophagy that is often difficult to separate from their roles in fusion, which is an area of intense research.…”

Section: The Role Of Fusion/fission Dysregulation In Age-related Cmentioning

confidence: 99%

Mitochondrial dysfunction in cardiac aging

Tocchi

Quarles

Basisty

et al. 2015

Biochimica et Biophysica Acta (BBA) - Bioenergetics

120

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Cardiovascular diseases are the leading cause of death in most developed nations. While it has received the least public attention, aging is the dominant risk factor for developing cardiovascular diseases, as the prevalence of cardiovascular diseases increases dramatically with increasing age. Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellular and molecular changes. Mitochondria play a great role in these processes, as cardiac function is an energetically demanding process. In this review, we examine mitochondrial dysfunction in cardiac aging. Recent research has demonstrated that mitochondrial dysfunction can disrupt morphology, signaling pathways, and protein interactions; conversely, mitochondrial homeostasis is maintained by mechanisms that include fission/fusion, autophagy, and unfolded protein responses. Finally, we describe some of the recent findings in mitochondrial targeted treatments to help meet the challenges of mitochondrial dysfunction in aging.

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“…Fission is also executed by dynamin-related protein 1 (Drp-1), a cytosolic protein that is recruited to the mitochondrial surface by phosphorylation in response to oxidative stress. It has also been well established that mitochondrial fragmentation occurs in heart failure [12–14]. …”

Section: Introductionmentioning

confidence: 99%

Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure

et al. 2017

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In addition to their anti-bacterial action, tetracyclines also have complex biological effects, including the modification of mitochondrial protein synthesis, metabolism and gene-expression. Long-term clinical studies have been performed using tetracyclines, without significant side effects. Previous studies demonstrated that doxycycline (DOX), a major tetracyclin antibiotic, exerted a protective effect in animal models of heart failure; however, its exact molecular mechanism is still unknown. Here, we provide the first evidence that DOX reduces oxidative stress—induced mitochondrial fragmentation and depolarization in H9c2 cardiomyocytes and beneficially alters the expression of Mfn-2, OPA-1 and Drp-1 –the main regulators of mitochondrial fusion and fission—in our isoproterenol (ISO)–induced heart failure model, ultimately decreasing the severity of heart failure. In mitochondria, oxidative stress causes a shift toward fission which leads to mitochondrial fragmentation and cell death. Protecting mitochondria from oxidative stress, and the regulation of mitochondrial dynamics by drugs that shift the balance toward fusion, could be a novel therapeutic approach for heart failure. On the basis of our findings, we raise the possibility that DOX could be a novel therapeutic agent in the future treatment of heart failure.

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Heart Failure and Mitochondrial Dysfunction

Cited by 77 publications

References 132 publications

Sepsis-induced myocardial dysfunction: pathophysiology and management

Sepsis-induced myocardial dysfunction: pathophysiology and management

Mitochondrial dysfunction in cardiac aging

Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure

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