Pressure Overload–Induced Alterations in Fibrillar Collagen Content and Myocardial Diastolic Function

Abstract

Background-Chronic pressure overload causes myocardial hypertrophy, increased fibrillar collagen content, and abnormal diastolic function. We hypothesized that one determinant of these pressure overload-induced changes is the extracellular processing of newly synthesized procollagen into mature collagen fibrils. We further hypothesized that secreted protein acidic and rich in cysteine (SPARC) plays a key role in post-synthetic procollagen processing in normal and pressure-overloaded myocardium. Methods and Results-To determine whether pressure overload-induced changes in collagen content and diastolic function are affected by the absence of SPARC, age-matched wild-type (WT) and SPARC-null mice underwent either transverse aortic constriction (TAC) for 4 weeks or served as nonoperated controls. Left ventricular (LV) collagen content was measured histologically by collagen volume fraction, collagen composition was measured by hydroxyproline assay as soluble collagen (1 mol/L NaCl extractable) versus insoluble collagen (mature cross-linked collagen), and collagen morphological structure was examined by scanning electron microscopy. SPARC expression was measured by immunoblot. LV, myocardial, and cardiomyocyte structure and function were assessed by echocardiographic, papillary muscle, and isolated cardiomyocyte studies. In WT mice, TAC increased LV mass, SPARC expression, myocardial diastolic stiffness, fibrillar collagen content, and soluble and insoluble collagen. In SPARC-null mice, TAC increased LV mass to an extent similar to WT mice. In addition, in SPARC-null mice, TAC increased fibrillar collagen content, albeit significantly less than that seen in WT TAC mice. Furthermore, the proportion of LV collagen that was insoluble was less in the SPARC-null TAC mice (86Ϯ2%) than in WT TAC mice (99Ϯ2%, PϽ0.05), and the proportion of collagen that was soluble was greater in the SPARC-null TAC mice (14Ϯ2%) than in WT TAC mice (1Ϯ2%, PϽ0.05) As a result, myocardial diastolic stiffness was lower in SPARC-null TAC mice (0.075Ϯ0.005) than in WT TAC mice (0.045Ϯ0.005, PϽ0.05). Conclusions-The absence of SPARC reduced pressure overload-induced alterations in extracellular matrix fibrillar collagen and diastolic function. These data support the hypothesis that SPARC plays a key role in post-synthetic procollagen processing and the development of mature cross-linked collagen fibrils in normal and pressure-overloaded myocardium. (Circulation. 2009;119:269-280.)

CD4 + T Cells Promote the Transition From Hypertrophy to Heart Failure During Chronic Pressure Overload

“…21 Our results showed the presence of abundant birefringent fibers in WT mice after TAC. Collagen fibers, faintly detectable in RAG2KO mice, were strongly visible in T cell-reconstituted mice (RAG2KO+CD3; Figure 6E).…”

SPARC regulates collagen interaction with cardiac fibroblast cell surfaces

“…Notably, a significant decrease in fibrillar collagen and a diminished capacity to mount a robust fibrotic response have been found in these mice. In the heart, the function of the matricellular protein SPARC has been recognized as a critical component in the control of interstitial collagen content under normal conditions and in fibrotic conditions such as response to infarction and pressure overload hypertrophy (5,26). This study represents the first examination of the cellular mechanisms by which SPARC influences cardiac fibroblast proliferation and collagen deposition.…”

“…In fact, increased expression of SPARC within older mammalian hearts has been shown to contribute to increased collagen content and associated increases in stiffness indicative of the aged myocardium (6,17). Previous reports (5,26) have demonstrated the importance of SPARC in the fibrotic response to pressure overload and myocardial infarction. These studies highlight the dichotomy of collagen content in the heart: whereas the absence of SPARC improved diastolic function in response to pressure overload, SPARC-null mice had increased rupture after myocardial infarction.…”

Simultaneous exposure to estrogen and androgen resulted in feminization and endocrine disruption

“…Some of the highly expressed ribosome genes are also reported to be involved in abiotic stress responses . sparc has been reported to play a key role in post-synthetic procollagen processing in normal and pressure-overloaded myocardium of mice (Bradshaw et al 2009). The expression of wt1b, an epicardial gene in zebrafish, is responsive to heart injury (Itou et al 2012).…”