Adding insult to injury - Inflammation at the heart of cardiac fibrosis

Smolgovsky, Sasha; Ibeh, Udoka; Tamayo, Tatiana Peña; Alcaide, Pilar

doi:10.1016/j.cellsig.2020.109828

Cited by 33 publications

(20 citation statements)

References 110 publications

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“…Our mRNA data suggest that there was increased inflammation in our AngII model of hypertension in mice and this was reduced by dabrafenib ( Figure 3 G). This remains to be confirmed at the protein level, but increased inflammation is likely to promote cardiac fibrosis [ 47 ]. Increasing cardiac fibrosis adds to the workload on the heart, potentially causing further cardiomyocyte hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

The anti-cancer drug dabrafenib is not cardiotoxic and inhibits cardiac remodelling and fibrosis in a murine model of hypertension

et al. 2021

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Raf kinases signal via extracellular signal-regulated kinases 1/2 (ERK1/2) to drive cell division. Since activating mutations in BRAF (B-Raf proto-oncogene, serine/threonine kinase) are highly oncogenic, BRAF inhibitors including dabrafenib have been developed for cancer. Inhibitors of ERK1/2 signalling used for cancer are cardiotoxic in some patients, raising the question of whether dabrafenib is cardiotoxic. In the heart, ERK1/2 signalling promotes not only cardiomyocyte hypertrophy and is cardioprotective but also promotes fibrosis. Our hypothesis is that ERK1/2 signalling is not required in a non-stressed heart but is required for cardiac remodelling. Thus, dabrafenib may affect the heart in the context of, for example, hypertension. In experiments with cardiomyocytes, cardiac fibroblasts and perfused rat hearts, dabrafenib inhibited ERK1/2 signalling. We assessed the effects of dabrafenib (3 mg/kg/d) on male C57BL/6J mouse hearts in vivo. Dabrafenib alone had no overt effects on cardiac function/dimensions (assessed by echocardiography) or cardiac architecture. In mice treated with 0.8 mg/kg/d angiotensin II (AngII) to induce hypertension, dabrafenib inhibited ERK1/2 signalling and suppressed cardiac hypertrophy in both acute (up to 7 d) and chronic (28 d) settings, preserving ejection fraction. At the cellular level, dabrafenib inhibited AngII-induced cardiomyocyte hypertrophy, reduced expression of hypertrophic gene markers and almost completely eliminated the increase in cardiac fibrosis both in interstitial and perivascular regions. Dabrafenib is not overtly cardiotoxic. Moreover, it inhibits maladaptive hypertrophy resulting from AngII-induced hypertension. Thus, Raf is a potential therapeutic target for hypertensive heart disease and drugs such as dabrafenib, developed for cancer, may be used for this purpose.

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Section: Discussionmentioning

confidence: 99%

The anti-cancer drug dabrafenib is not cardiotoxic and inhibits cardiac remodelling and fibrosis in a murine model of hypertension

et al. 2021

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“…Replacement of necrotic cardiomyocytes (as a result of myocarditis, vasculitis, and microinfarctions) by fibroblasts appears to be the main mechanism of fibrosis in COVID-19 patients. In addition, cytokine storm and infiltration of the myocardium with immune cells, which can potentially initiate fibroblast to myofibroblast conversion and subsequent matrix remodeling, are among other possible mechanisms of fibrosis in these patients ( 84 ).…”

Section: Cardiovascular Complications Of Covid-19mentioning

confidence: 99%

Cardiovascular complications of COVID-19

Farshidfar¹,

Koleini²,

Ardehali³

2021

JCI Insight

115

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The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) has resulted in an unprecedented pandemic that has been accompanied by a global health crisis. Although the lungs are the main organs involved in COVID-19, systemic disease with a wide range of clinical manifestations also develops in SARS-CoV-2-infected patients. One of the major systems affected by this virus is the cardiovascular system. The presence of pre-existing cardiovascular disease increases mortality in COVID-19 patients, and cardiovascular injuries, including myocarditis, cardiac rhythm abnormalities, endothelial cell injury, thrombotic events, and myocardial interstitial fibrosis, are observed in some COVID-19 patients. The underlying pathophysiology of COVID-19-associated cardiovascular complications is not fully understood, although direct viral infection of myocardium and cytokine storm have been suggested as possible mechanisms of myocarditis. In this review, we summarize available data on SARS-CoV-2-related cardiac damage and discuss potential mechanisms of cardiovascular implications of this rapidly spreading virus.

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“…Although the underlying mechanisms of cardiac involvement in COVID-19 infection remain to be fully elucidated, cardiac fibrosis occurs in tandem with local and systemic inflammatory responses [84]. Whilst these mechanisms are designed to facilitate healing following tissue damage, an excess of the inflammatory response along with the development of fibrotic tissue are pathological drivers for global organ damage.…”

Section: Gross Cardiac Pathology and Histopathologymentioning

confidence: 99%

Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement of the Cardiovascular System

Gaze¹

2021

Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions

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Since the emergence in China of coronavirus disease (COVID-19) in December 2019; the virus causing the pandemic has infected the human population in almost every country and territory on the globe. At the time of writing there are over 84 million confirmed cases of infection and over 1.8 million deaths globally. Rates of infection differ as does the number of severe cases and subsequent deaths between countries and continents. This is due in part to lockdown measures, social distancing and wearing of face coverings. It is also reflected by how healthcare systems record coronavirus deaths along with access to testing as well as tracking and tracing of infected individuals. Symptoms of COVID-19 include a novel persistent cough, fever and anosmia (loss of smell). In most cases, such symptoms are mild. A small proportion of those who become infected however, have a severe reaction to the disease affecting multiple organ systems and often require respiratory support in the intensive care setting. One such physiological system affected is the cardiovascular system. This is likely due to the increased number of ACE2 receptors in co-morbid cardiac pathologies. ACE2 receptors serve as the entry port for the coronavirus into human cells. Those individuals with underlying cardiovascular risk factors are therefore disproportionately at risk of COVID-19 infection. This chapter reviews the aetiology and epidemiology of the coronavirus infection; potential pathophysiological mechanisms of disease involving the cardiovascular system including the clinical utility of biomarkers, electrocardiography and echocardiography as well as autopsy cardiac pathology and histopathology.

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Adding insult to injury - Inflammation at the heart of cardiac fibrosis

Cited by 33 publications

References 110 publications

The anti-cancer drug dabrafenib is not cardiotoxic and inhibits cardiac remodelling and fibrosis in a murine model of hypertension

The anti-cancer drug dabrafenib is not cardiotoxic and inhibits cardiac remodelling and fibrosis in a murine model of hypertension

Cardiovascular complications of COVID-19

Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement of the Cardiovascular System

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