Pressure overload leads to an increased accumulation and activity of mast cells in the right ventricle

Abstract

Right ventricular (RV) remodeling represents a complex set of functional and structural adaptations in response to chronic pressure or volume overload due to various inborn defects or acquired diseases and is an important determinant of patient outcome. However, the underlying molecular mechanisms remain elusive. We investigated the time course of structural and functional changes in the RV in the murine model of pressure overload‐induced RV hypertrophy in C57Bl/6J mice. Using magnetic resonance imaging, we assessed the changes of RV structure and function at different time points for a period of 21 days. Pressure overload led to significant dilatation, cellular and chamber hypertrophy, myocardial fibrosis, and functional impairment of the RV. Progressive remodeling of the RV after pulmonary artery banding (PAB) in mice was associated with upregulation of myocardial gene markers of hypertrophy and fibrosis. Furthermore, remodeling of the RV was associated with accumulation and activation of mast cells in the RV tissue of PAB mice. Our data suggest possible involvement of mast cells in the RV remodeling process in response to pressure overload. Mast cells may thus represent an interesting target for the development of new therapeutic approaches directed specifically at the RV.

FHL-1 is not involved in pressure overload-induced maladaptive right ventricular remodeling and dysfunction

“…All these mechanisms lead to RV dysfunction, as demonstrated by a reduced contractility index and TAPSE and elevated RVDEP. Similar observations were already made for C57/ BL6 mice [14,28].…”

“…We confirmed the induction of chronic pressure overload RV hypertrophy and fibrosis by PAB in outbred Swiss mice as already described for inbred C57BL/6 J mice and rats [13,14,25,28]. However, in contrast to the LV, FHL-1 −/− mice did not show maintenance of the RV function and blunted hypertrophic response, indicating that pathways causing left heart maladaptation cannot always be transferred to the RV.…”

“…To assess the in vivo impact of FHL-1, regulation of FHL-1 was assessed in right ventricular tissue homogenate samples from C57/BL6 mice subjected to either PAB or sham surgery for 1 week, 2 weeks, and 3 weeks. Samples were obtained from a previous study [28].…”

“…Right ventricular pressure overload was induced by PAB in FHL-1 −/− and WT Swiss mice as previously described [28]. Briefly, buprenorphine hydrochloride (Temgesic ® , 0.1 mg/ kg bw, Essex Pharma GmbH, Munich, Germany) was administered s.c. as an analgesic prior to operation.…”

“…In a previous study, FHL-1 was identified as a key protein in a biomechanical stress sensing complex in the left heart as FHL-1 deficient mice exhibited an attenuated hypertrophic signal transduction and preserved LV function after TAC [37]. To decipher the role of FHL-1 in hypertrophic signaling leading to right heart hypertrophy, we first assessed the FHL-1 expression in an in vivo model of pressure overloadinduced right heart hypertrophy caused by PAB in C57/BL6 mice [28]. Pressure overload led to an increase in FHL-1 mRNA expression in the RV.…”