Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress

Chintalgattu, Vishnu; Ai, Di; Langley, Robert R.; Jian-hu, Zhang; Bankson, James A.; Shih, Tiffany; Reddy, Anilkumar K.; Coombes, Kevin R.; Daher, Iyad N.; Pati, Shibani; Patel, Shalin; Pocius, Jennifer; Taffet, George E.; Buja, L. Maximilian; Entman, Mark L.; Khakoo, Aarif Y.

doi:10.1172/jci39434

Cited by 174 publications

(146 citation statements)

References 55 publications

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“…39,40,45 Kerkela et al 40 demonstrated that the cardiotoxicity of TKIs was an unanticipated side effect of inhibition of c-Abl, a common characteristics of TKIs used in the treatment of CML. In addition, Chintalgattu et al 46 reported that cardiomyocyte platelet-derived growth factor receptor-beta is a regulator of the compensatory cardiac response to pressure overload-induced stress, suggesting that inhibition of platelet-derived growth factor pathway may be at least in part responsible for cardiotoxicity due to TKIs. Accumulated evidence indicates that receptors of tyrosine kinases (RTKs) play an important role in the pathogenesis of PAH, and inhibition of some specific RTK signaling may represent an attractive treatment for the disease.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

et al. 2012

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Background-The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. Methods and Results-This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (nϭ2) or calcium channel blocker (nϭ1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (Յ20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Conclusions-Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib. (Circulation. 2012;125:2128-2137.)

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Section: Discussionmentioning

confidence: 99%

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

et al. 2012

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“…2008; Chintalgattu et al. 2010). Sham‐operated EC‐MR +/+ and EC‐MR −/− mice underwent the same procedure but without constriction.…”

Section: Methodsmentioning

confidence: 99%

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

et al. 2017

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Heart Failure (HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor (MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF. However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells (EC), in which aldosterone induces the expression of intercellular adhesion molecule 1 (ICAM‐1). Recently, we reported that ICAM‐1 regulates cardiac inflammation and cardiac function in mice subjected to transverse aortic constriction (TAC). Whether MR specifically in endothelial cells (EC) contributes to the several mechanisms of pathological cardiac remodeling and cardiac dysfunction remains unclear. Basal cardiac function and LV dimensions were comparable in mice with MR selectively deleted from ECs (EC‐MR −/−) and wild‐type littermate controls (EC‐MR +/+). MR was specifically deleted in heart EC, and in EC‐containing tissues, but not in leukocytes of TAC EC‐MR −/− mice. While EC‐MR −/− TAC mice showed preserved systolic function and some alterations in the expression of fetal genes, the proinflammatory cytokine TNF α and the endothelin receptors in the LV as compared to EC‐MR +/+ TAC mice, no difference was observed between both TAC groups in overall cardiac hypertrophy, ICAM‐1 LV expression and leukocyte infiltration, cardiac fibrosis or capillary rarefaction, all hallmarks of pathological cardiac remodeling. Our data indicate that EC‐MR contributes to the transition of cardiac hypertrophy to systolic dysfunction independently of other maladaptive changes induced by LV pressure overload.

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“…Others demonstrate mild symptoms which may be difficult to differentiate from fatigue due to the TKI or the tumor itself (20). This toxicity is not completely understood, but platelet-derived growth factor receptor-β (PDGFR-β) inhibition has been implicated as playing a role in the response to pressure overload-induced stress (21).…”

Section: Adverse Eventsmentioning

confidence: 99%

Response to sorafenib treatment in advanced metastatic thyroid cancer

Pitoia

2014

Arq Bras Endocrinol Metab

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Objective: To investigate the efficacy of sorafenib in progressive radioiodine resistant metastatic thyroid carcinoma. Subjects and methods: Off-label observational study. Sorafenib 400 mg twice daily was evaluated. Therapy duration was 12 ± 3 months (range 6-16 months). Results: Eight patients were included (seven papillary, one insular variant). The eight patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. One patient showed a partial response with tumor regression of -35%, six months after the beginning of the treatment; five patients exhibited stable disease and two patients had progressive disease and died. Thyroglobulin decreased within 4 weeks in all patients by 50% ± 23%. Adverse events: one patient had heart failure, and recovered after sorafenib withdrawal. However, she died five months later of sudden death. Conclusion: These data suggest a possible role for sorafenib in the treatment of progressive metastatic DTC. Adverse event are usually manageable, but severe ones may appear and these patients should be strictly controlled. Arq Bras Endocrinol Metab. 2014;58(1):37-41 Keywords Metastasis; sorafenib; thyroid; cancer RESUMO Objetivo: Investigar a eficácia do sorafenibe no carcinoma de tireoide metastático progressivo e refratário à iodoterapia. Sujeitos e métodos: Estudo observacional do efeito do sorafenibe off-label administrado 400 mg duas vezes ao dia. A duração da terapia foi de 12 ± 3 meses (variação de 6-16 meses). Resultados: Oito pacientes foram incluídos (sete com variante papilífera e um com variante insular). Os oito pacientes que preencheram os critérios do estudo receberam o sorafenibe 400 mg por via oral duas vezes por dia até progressão da doença ou toxicidade inaceitável. Um paciente apresentou uma resposta parcial com regressão tumoral da lesão alvo de 35% seis meses após o início do tratamento; cinco pacientes apresentaram doença estável e dois pacientes progrediram e morreram. A tireoglobulina diminuiu 50% ± 23% em 4 semanas em todos os pacientes. Eventos adversos: um paciente teve insuficiência cardíaca e morreu por morte súbita cinco meses após a retirada do sorafenibe. Conclusão: Esses dados sugerem um possível papel para sorafenibe para o tratamento do CDT metastático progressivo. Arq Bras Endocrinol Metab. 2014;58(1):37-41Descritores

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Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress

Cited by 174 publications

References 55 publications

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

Response to sorafenib treatment in advanced metastatic thyroid cancer

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