Imatinib Mesylate Attenuates Myocardial Remodeling Through Inhibition of Platelet-Derived Growth Factor and Transforming Growth Factor Activation in a Rat Model of Hypertension

Abstract

The spontaneously hypertensive rat (SHR) is a genetically hypertensive rat model used to study human essential Abstract-Imatinib mesylate is a specific tyrosine kinase inhibitor that may block the platelet-derived growth factor and transforming growth factor pathways. These pathways are known to provoke fibroblast activation. We evaluated whether imatinib, by inhibiting these pathways, prevents diastolic dysfunction and attenuates myocardial remodeling using spontaneously hypertensive rats (SHRs). Eight-week-old male SHRs were randomly assigned to either imatinib treatment group (30 mg/kg per day; n=10; SHR-I) or hypertensive control group (distilled water, n=10; SHR-C). Wistar-Kyoto rats were used as normal controls (n=10). At 16 weeks, all rats underwent hemodynamic studies and Doppler echocardiography and then were euthanized. Their hearts were extracted for histopathologic, immunoblotting, and quantitative reverse transcriptase polymerase chain reaction analyses. Although imatinib did not affect blood pressure, it markedly reduced perivascular and interstitial fibrosis in the hearts of SHR. Echocardiogram showed that imatinib significantly reduced the left ventricular wall thickness (septal/posterior wall; SHR-C versus SHR-I, 18±1/19±2 versus 15±1/15±1 mm; P<0.001) and increased the E/A ratio (SHR-C versus SHR-I, 1.59±0.11 versus 1.84±0.16; P=0.001). Also, imatinib significantly reduced the mRNA expression of collagen type I, III, and platelet-derived growth factor receptor-β phosphorylation in the hearts of SHR. In addition, imatinib reduced collagen production by inhibiting the phosphorylation of c-abl and platelet-derived growth factor receptor-β in rat cardiac fibroblasts. In conclusion, these results suggest that imatinib could attenuate myocardial remodeling and improve left ventricular diastolic dysfunction in a hypertensive rat model by affecting platelet-derived growth factor and transforming growth factor-β1 pathway without the blood pressure-lowering

Imatinib attenuates cardiac fibrosis by inhibiting platelet-derived growth factor receptors activation in isoproterenol induced model

“…As a classical tyrosine kinase inhibitor, IMA inhibits the kinase activation of PDGFRs, c-Kit and c-Abl [14]. Recent studies demonstrated that the mechanisms of inhibition fibrosis by IMA were associated with blocking the activation of PDGFRs, and c-Abl [18–20]. Our results showed that IMA inhibited the activation of PDGFRα and PDGFRβ and decreased the mRNA expression of TGF-β1.…”

“…Many animal models have been used for the research of cardiac fibrosis, such as spontaneously hypertensive induced cardiac fibrosis model [18], the surgery models (myocardial infarction model, myocardial ischemia/reperfusion injury model, and transverse aortic constriction model) [45], and the induced models (desoxycorticosterone induced salt-sensitive hypertensive model [19], Ang II induced cardiac fibrosis model [46], and ISO induced cardiac fibrosis model [10]). However, the mechanisms of cardiac fibrosis in different models are diverse.…”

“…Jang et al reported that IMA attenuated cardiac fibrosis and improved diastolic cardiac dysfunction in a hypertensive rat model [18]. In the desoxycorticosterone induced salt-sensitive hypertensive rat model and the myocardial infarction rat model, IMA attenuated cardiac remodeling and reduced myocardial fibrosis [19, 20].…”

“…The anti-fibrotic effect of IMA has been demonstrated in pulmonary fibrosis, liver fibrosis, scleroderma fibroblasts, and renal fibroblasts [14–17]. IMA could attenuate cardiac fibrosis in spontaneously hypertensive rat model [18], desoxycorticosterone induced salt-sensitive hypertensive rat model [19], and myocardial infarction model [20]. The mechanism of IMA in different model is diverse.…”

Hypertension-linked mechanical changes of rat gut

“…However, other possibilities such as a direct effect of angiotensin II (ANG II) on the gut cannot be ruled out. ANG II has been shown to induce fibrosis and hypertrophy of vessels and heart tissue in rodent models of HTN [43], and these pathologies are also present in the SHR model [44]. Finally, changes in the gut may be indirect and could be induced by increase in blood pressure.…”