More than just a small left ventricle: the right ventricular fibroblast and ECM in health and disease

Abstract

Fibroblasts intricately organize and regulate the extracellular matrix (ECM) in cardiac health and disease. Excess deposition of ECM proteins causes fibrosis, resulting in disrupted signaling conduction and contributing to the development of arrhythmias and impaired cardiac function. Fibrosis is causally involved in cardiac failure in the left ventricle (LV). Fibrosis likely occurs in right ventricle (RV) failure, yet mechanisms remain unclear. Indeed, RV fibrosis is poorly understood with mechanisms often extrapolated from the LV to the RV. However, emerging data suggest that the LV and RV are distinct cardiac chambers and differ in regulation of the ECM and response to fibrotic stimuli. In the present review, we will discuss differences in ECM regulation in the healthy RV and LV. We will discuss the importance of fibrosis in the development of RV disease in pressure overload, inflammation, and aging. During this discussion, we will highlight mechanisms of fibrosis with respect to the synthesis of ECM proteins while acknowledging the importance of considering collagen breakdown. We will also discuss current knowledge of antifibrotic therapies in the RV and the need for additional research to help delineate the shared and distinct mechanisms of RV and LV fibrosis.

Keywords: aging; fibroblast; fibrosis; right ventricle.

Figure 1.

Proposed differences in the healthy extracellular matrix (ECM) in the left ventricle (LV) and right ventricle (RV) due to developmental changes in chamber composition. At birth, cellular composition of the RV and LV is likely similar. However, during development, more rapid growth of myocytes in the LV results in a lower composition of fibroblasts and collagen compared with the RV. The RV also has higher proportion of immune cells than the LV that may contribute to different fibrosis signaling pathways and collagen deposition.

Figure 2.

Fibrotic gene expression in response to pressure overload (PO) in the left ventricle [LV; transaortic constriction (TAC)] and right ventricle [RV; pulmonary artery banding (PAB)]. A: periostin (POSTN) expression was higher in the PO RV and unchanged in the PO LV. B: α-smooth muscle actin (α-SMA) expression was unchanged in either PO model. C and D: expression of Col1a1 (C) and Col3 (D) were higher in the PO RV and unchanged in the PO LV compared with respective shams. E: expression of matrix metalloproteinase 2 (MMP2) was lower in the PO LV compared with sham and was unchanged in the RV; n = 4 per group. *P < 0.05, PO vs. sham within ventricle. #P < 0.1, PO vs. sham within ventricle. Gene expression was quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in ∼4-mo-old male C57Bl6/J mice. White bars, sham; gray bars, PO. Data are expressed as means ± SE. Adult (∼4–6 mo) C57/BL/6J male mice were subjected to either PAB (80) or TAC (81) surgery. Sham mice underwent anesthesia and thoracotomy without suturing the pulmonary artery or the aorta. Four weeks after surgery, the RV was dissected from the LV (PAB) and the LV + septum from the RV (TAC) and ventricles were flash frozen. Previous reports have not demonstrated significant effects of TAC or PAB on the opposite ventricle over this time course (80). A limitation of these experiments is that we have no direct measure of the degree of pressure overload that is induced by either PAB or TAC. qRT-PCR was performed as previously described (82).

Figure 3.

Fibrosis and fibrotic gene expression in adult (4 mo) and aged (18 mo) male and female C5lBl6/J mice. A and B: representative Picrosirius red collagen histology of adult and aged right ventricle (RV) and left ventricle (LV) (A), demonstrating higher collagen content in the aged RV and LV compared with adult matched ventricles (B). ^Higher percent area of collagen in the LV compared with the RV. C: periostin (POSTN) expression was unchanged in either ventricle with age. α-Smooth muscle actin (α-SMA; D), Col1a1 (E), and Col3 (F) expression were higher in the aged RV compared with adult but unchanged in the LV (interaction age × ventricle, P = 0.07). E: Col1a1 expression was more robustly upregulated in the RV with age compared with the LV (interaction, age × ventricle). G: expression of matrix metalloproteinase 2 (MMP2) was lower in the aged LV compared with adult but was unchanged with age in the RV. *P < 0.05, adult vs. aged within ventricle. ^P < 0.05 main effect of ventricle (LV > RV). $P < 0.05 interaction age × ventricle. Picrosirius red staining was performed as previously described (94). Gene expression was quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) (82). White bars, adult; gray bars, aged. Data are expressed as means ± SE.

Figure 4.

Summary of current understanding of right ventricle (RV) fibrosis. The healthy RV extracellular matrix (ECM) is under constant regulation to balance collagen synthesis and degradation to maintain RV function and integrity. However, cardiac stress from pathological conditions such as pressure overload, inflammation, or aging alters cell composition and extensively modifies the ECM to accumulate myofibroblasts and ECM proteins. Periostin is consistently upregulated in RV disease and likely plays an important role in RV remodeling. Myofibroblast differentiation, matrix metalloproteinase (MMP) activity, and collagen degradation or collagen cross-linking remain poorly understood in the fibrotic RV.