Abstract
Reactive cardiac fibrosis resulting from chronic pressure overload (PO) compromises ventricular function and contributes to congestive heart failure. We explored whether nonreceptor tyrosine kinases (NTKs) play a key role in fibrosis by activating cardiac fibroblasts (CFb), and could potentially serve as a target to reduce PO-induced cardiac fibrosis. Our studies were carried out in PO mouse myocardium induced by transverse aortic constriction (TAC). Administration of a tyrosine kinase inhibitor, dasatinib, via an intraperitoneally implanted mini-osmotic pump at 0.44 mg/kg/day reduced PO-induced accumulation of extracellular matrix (ECM) proteins and improved left ventricular geometry and function. Furthermore, dasatinib treatment inhibited NTK activation (primarily Pyk2 and Fak) and reduced the level of FSP1 positive cells in the PO myocardium. In vitro studies using cultured mouse CFb showed that dasatinib treatment at 50 nM reduced: (i) extracellular accumulation of both collagen and fibronectin, (ii) both basal and PDGF-stimulated activation of Pyk2, (iii) nuclear accumulation of Ki67, SKP2 and histone-H2B and (iv) PDGF-stimulated CFb proliferation and migration. However, dasatinib did not affect cardiomyocyte morphologies in either the ventricular tissue after in vivo administration or in isolated cells after in vitro treatment. Mass spectrometric quantification of dasatinib in cultured cells indicated that the uptake of dasatinib by CFb was greater that that taken up by cardiomyocytes. Dasatinib treatment primarily suppressed PDGF but not insulin-stimulated signaling (Erk versus Akt activation) in both CFb and cardiomyocytes. These data indicate that dasatinib treatment at lower doses than that used in chemotherapy has the capacity to reduce hypertrophy-associated fibrosis and improve ventricular function.
Highlights
Cardiac fibrosis is one of the detrimental factors that contributes to heart failure during increased cardiac workload under conditions such as hypertension or aortic stenosis
We explored whether administration of dasatinib, which is used to treat patients with chronic myeloid leukemia (CML), can suppress pressure overload (PO)-induced cardiac fibrosis
Several studies report a strong correlation between myocardial fibrosis and ventricular dysfunction in patients diagnosed with congestive heart failure (CHF) [1,2,3,4,5]
Summary
Cardiac fibrosis is one of the detrimental factors that contributes to heart failure during increased cardiac workload under conditions such as hypertension or aortic stenosis. Newer approaches at the molecular level are needed to address this problem In this context, identification of specific pathways that promote the mitogenic, secretory and proliferative potential of cardiac fibroblasts (CFb) may serve as a unique target for treating cardiac fibrosis. We have recently reported that CFb from β3-/- integrin mice induced with hypertrophic stimulation exhibited a low fibrotic status (as seen by reduced collagen and fibronectin accumulation in the ECM) in the myocardium [9]. This indicates that β3 integrin might mediate mitogenic and proliferative signaling in CFb of PO myocardium. Dasatinib treatment reduced ECM deposition and improved ventricular function and geometry during PO, indicating that this drug used at appropriate lower doses may offer therapeutic benefits to patients with chronic PO
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