Differential Expression of Matrix Metalloproteinases and Tissue Inhibitors and Extracellular Matrix Remodeling in Aortic Regurgitant Hearts

Abstract

Objectives: Myocardial fibrosis in experimental aortic regurgitation (AR) features abnormal fibronectin with normal collagen content, but the relevant degradative processes have not been assessed. Methods: To elucidate these degradative processes, mRNA (Northern) and protein levels (Western) of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), as well as MMP activity (zymography), were measured in cardiac fibroblasts (CF) from New Zealand white rabbits with experimental AR paired with normals (NL). Collagen and fibronectin were quantified by immunohistochemical staining. Results: In AR CF versus NL CF, MMP-2 and -14 mRNA and protein were increased (both p < 0.005), while TIMPs 1–3 were slightly decreased (p < 0.05–0.005; TIMP-4 undetectable). Gelatinase activity in AR CF was 1.7 times that in NL CF (p < 0.005); fibronectinase activity was unaffected. The Jun N-terminal kinase (JNK) inhibitor SP600125 suppressed MMP-2 protein (0.4-fold, p < 0.05) and mRNA (0.7-fold, p < 0.005) in AR CF; MMP-2 levels in NL CF were unaffected. AR MMP-9 mRNA, protein and activity were low and indistinguishable from NL. In left ventricular tissue, fibronectin was increased 1.9-fold (AR vs. NL, p < 0.05). Total AR collagen was indistinguishable from NL, but the collagen III to collagen I isoform ratio decreased (0.4-fold, p < 0.05). Conclusions: Collagen is relatively deficient in AR fibrosis, due at least in part to upregulated MMPs and downregulated TIMPs; fibronectinase is unaltered. JNK-dependent regulation may stimulate both MMP-2 and fibronectin expression in AR, providing a potential therapeutic target.

Animal Models of Heart Failure

“…However, the induction of LV volume overload either through the creation of aortic insufficiency or an aortocaval fistula has been described. [21][22][23][24][25][26] A retrograde catheter technique has been used in rabbits to induce damage to the aortic valve with significant aortic regurgitation and thereby LV volume overload. In this model of LV volume overload, LV dilation and eccentric LVH occurs over a period of weeks to months with accompanying increased LV filling pressures and the manifestations of HF.…”

“…In this model of LV volume overload, LV dilation and eccentric LVH occurs over a period of weeks to months with accompanying increased LV filling pressures and the manifestations of HF. 21,22 LV volume overload can also be induced by creation of a small bridge between the abdominal aorta and inferior vena cava, thereby inducing a functional aortocaval fistula. [21][22][23][24][25][26] Detailed LV morphometric studies have been performed in the rat model of aortocaval fistula and have provided some of the early insight into the level of LV myocardial and myocyte remodeling that occurs with chronic volume overload.…”

“…21,22 LV volume overload can also be induced by creation of a small bridge between the abdominal aorta and inferior vena cava, thereby inducing a functional aortocaval fistula. [21][22][23][24][25][26] Detailed LV morphometric studies have been performed in the rat model of aortocaval fistula and have provided some of the early insight into the level of LV myocardial and myocyte remodeling that occurs with chronic volume overload. 23,24 This rat model of LV volume overload has been successfully used to examine the effects of pharmacological interruption of signaling and proteolytic pathways that likely contribute to LV remodeling and failure secondary to a volume overload.…”

Survival after Aortic Valve Replacement for Aortic Regurgitation: Prediction from Preoperative Contractility Measurement

“…The data from this study support this hypothesis. Increasing emphasis has been placed on myocardial biology to compensate for the prognostic inadequacies of conventional size and performance descriptors in AR [47][48][49][50]; intrinsic contractility may prove an integrator of these various biological responses.…”

A Multimarker Study of Degenerative Aortic Valve Disease: Stenoinsufficiency Shows More Indices of Bad Prognosis

“…These subjects were characterized by a higher percentage of tissue fibrosis and by a profibrotic balance of MMPs and TIMPs, both in plasma and in tissue, probably due to the pathological deposition of substitutive fibrosis. Otherwise, control subjects with annulo-ectatic AR presented an antifibrotic trend, as described by Truter et al [27]. Moreover, the echocardiographic parameters of left ventricular dysfunction, the increased mass index and the increased peak pulmonary pressure suggested an incipient heart failure in these subjects with ASI.…”