CTGF knockout does not affect cardiac hypertrophy and fibrosis formation upon chronic pressure overload

Fontes, Magda S.C.; Kessler, Elise L.; Stuijvenberg, Leonie van; Brans, Maike A.D.; Falke, Lucas L.; Kok, Bart; Leask, Andrew; Rijen, Harold V.M. van; Vos, Marc A.; Goldschmeding, Roel; Veen, Toon A.B. van

doi:10.1016/j.yjmcc.2015.09.015

Cited by 40 publications

(41 citation statements)

References 33 publications

(57 reference statements)

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“…In contrast to the beneficial effects of CTGF inhibition in TAC [13] and PKCε-induced DCM (this report), targeted deletion of most CTGF in adult cardiomyocytes and nonmuscle cells did not appear to prevent the functional changes or fibrosis induced by TAC [14, 15], or overexpression of a constitutively active form of TGF-β [14]. However, in some experiments, the reported data exhibited trends consistent with a beneficial effect of loss of CTGF function on fibrillar collagen gene expression [15], but were not significant at the small group sizes examined [14].…”

Section: Discussionmentioning

confidence: 74%

“…However, in some experiments, the reported data exhibited trends consistent with a beneficial effect of loss of CTGF function on fibrillar collagen gene expression [15], but were not significant at the small group sizes examined [14]. Thus, although further investigation is necessary to understand the differences observed from the various animal models used, the cumulative data suggest that inhibition of CTGF in patients with cardiovascular disease is unlikely to be harmful and instead, could provide a significant benefit to patients with DCM.…”

Section: Discussionmentioning

confidence: 88%

“…CTGF is also involved in initiating processes underlying fibrosis of several organs and tissues, including the heart [6]. However, data on its regulation and its functional role in the pathogenesis of cardiac remodeling and fibrosis in the failing heart are limited and controversial [7-15]. …”

Section: Introductionmentioning

confidence: 99%

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Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy

Koshman

Sternlicht

Kim

et al. 2015

Journal of Molecular and Cellular Cardiology

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Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective Tissue Growth Factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to cardiac fibrosis, heart failure, and increased mortality. Beginning at 3 months of age, PKCε mice were treated with a neutralizing monoclonal antibody to CTGF (FG-3149) for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic function in PKCε mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling were elevated in PKCε mice, but significantly decreased by CTGF inhibition. However total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCε mice suggests that CTGF inhibition may benefit patients with DCM. Additional studies to explore this potential are warranted.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 88%

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Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy

Koshman

Sternlicht

Kim

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…Moreover, in a rabbit model of eccentric hypertrophy, where strains and workload are expected to be high throughout the LV wall, CTGF was also found to be overexpressed 3. Of note is that recent studies question the importance of CTGF in cardiac structural remodelling, indicating that while it is an important biomarker of myocardial remodelling, it most likely does not play a decisive role in this process24, 25 …”

Section: Discussionmentioning

confidence: 99%

Local microRNA‐133a downregulation is associated with hypertrophy in the dyssynchronous heart

et al. 2017

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AimsLeft bundle branch block (LBBB) creates considerable regional differences in mechanical load within the left ventricle (LV). We investigated expression of selected microRNAs (miRs) in relation to regional hypertrophy and fibrosis in LBBB hearts and their reversibility upon cardiac resynchronization therapy (CRT).Methods and resultsEighteen dogs were followed for 4 months after induction of LBBB, 10 of which received CRT after 2 months. Five additional dogs served as control. LV geometric changes were determined by echocardiography and myocardial strain by magnetic resonance imaging tagging. Expression levels of miRs, their target genes: connective tissue growth factor (CTGF), serum response factor (SRF), nuclear factor of activated T cells (NFATc4), and cardiomyocyte diameter and collagen deposition were measured in the septum and LV free wall (LVfw). In LBBB hearts, LVfw and septal systolic circumferential strain were 200% and 50% of control, respectively. This coincided with local hypertrophy in the LVfw. MiR‐133a expression was reduced by 33% in the LVfw, which corresponded with a selective increase of CTGF expression in the LVfw (279% of control). By contrast, no change was observed in SRF and NFATc4 expression was decreased in LBBB hearts. CRT normalized strain patterns and reversed miR‐133a and CTGF expression towards normal, expression of other miRs, related to remodelling, such as miR‐199b and miR‐155f, were not affected.ConclusionsIn the clinically relevant large animal model of LBBB, a close inverse relation exists between local hypertrophy and miR‐133a. Reduced miR‐133a correlated with increased CTGF levels but not with SRF and NFATc4.

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“…CTGF and downstream collagen I production by ANG II is mediated through an ERK/p38MAPK/Smad3 axis (889) and Rho kinase (887). While CTGF/CCN2 has also been implicated in ANG II-induced renal fibrosis, its role in general fibrotic responses has been challenged recently (286). HIF-1␣ has been implicated in ANG II-induced renal fibrosis (1274).…”

Section: Renal Fibrosis and Inflammationmentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

812

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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CTGF knockout does not affect cardiac hypertrophy and fibrosis formation upon chronic pressure overload

Cited by 40 publications

References 33 publications

Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy

Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy

Local microRNA‐133a downregulation is associated with hypertrophy in the dyssynchronous heart

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

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