Mechanisms of novel cardioprotective functions of CCN2/CTGF in myocardial ischemia-reperfusion injury

Abstract

CCN2/connective tissue growth factor (CTGF), a CCN family matricellular protein repressed in healthy hearts after birth, is induced in heart failure of various etiologies. Multiple cellular and biological functions have been assigned to CCN2/CTGF depending on cellular context. However, the functions and mechanisms of action of CCN2/CTGF in the heart as well as its roles in cardiac physiology and pathophysiology remain unknown. Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) were generated and compared with nontransgenic littermate control (NLC) mice. Tg-CTGF mice displayed slightly lower cardiac mass and inconspicuous increase of myocardial collagen compared with NLC mice but no evidence of contractile dysfunction. Analysis of the myocardial transcriptome by DNA microarray revealed activation of several distinct gene programs in Tg-CTGF hearts involved in cardioprotection and growth inhibition. Indeed, Tg-CTGF mice subjected to ischemia-reperfusion injury by in situ transient occlusion of the left anterior descending coronary artery in vivo displayed reduced vulnerability with markedly diminished infarct size. These findings were recapitulated in isolated hearts perfused with recombinant human (h)CTGF before the ischemia-reperfusion procedure. Consistently, Tg-CTGF hearts, as well as isolated adult cardiac myocytes exposed to recombinant hCTGF, displayed enhanced phosphorylation and activity of the Akt/p70S6 kinase/GSK-3β salvage kinase pathway and induction of several genes with reported cardioprotective functions. Inhibition of Akt activities also prevented the cardioprotective phenotype of hearts from Tg-CTGF mice. This report provides novel evidence that CTGF confers cardioprotection by salvage phosphokinase signaling leading to inhibition of GSK-3β activities, activation of phospho-SMAD2, and reprogramming of gene expression.

The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

“…Different strategies for blocking CCN2 activity have proven beneficial effects in fibrotic-related pathologies, including renal diseases, 12 whereas CCN2 overexpression induces cardioprotection. 17,18 Our results set out that IL17A neutralization block inflammatory events caused by the C-terminal module of CCN2 in the kidney, and suggest that IL-17A targeting could be a better therapeutic option than CCN2 blockers for human use in inflammatory diseases.…”

“…13,14 Therapeutic approaches that selectively block endogenous CCN2 activity have proven beneficial effects in fibrotic-related diseases, including experimental lung, liver, vascular, and renal diseases, and some authors have suggested that CCN2 could be a therapeutic target for fibrosis. [12][13][14][15][16] However, cardiac CCN2 overexpression conferred cardioprotection in Angiotensin II-infused mice and in ischemia-reperfusion injury, 17,18 showing that CCN2 exerts protective effects in some pathological settings. These data suggest that before using CCN2 blockers in humans, it is necessary to fully understand the in vivo biological functions of this protein and its fragments.…”

Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice

“…Elution of hydroxyproline was verified and quantified by coelution with known amounts of derivatized hydroxyproline standards (Fluka, Buchs, Switzerland). The relation of myocardial hydroxyproline contents to myocardial collagen has been previously reported (1).…”

Myocardial Extracellular Matrix

“…CCN-2 is the most comprehensively studied member of the CCN family in relation to cardiac disease. The evident upregulation of CCN-2 in response to MI 258 and pressure overload [259][260][261] is essential for potentiating TGF-β signaling, stimulating survival of cardiomyocytes, and enabling proper angiogenic and fibrotic responses, both in MI [262][263][264] and in response to pressure overload. [265][266][267][268][269] In contrast, CCN-5 overexpression diminishes the hypertrophic and fibrotic response after pressure overload by influencing TGF-β/ SMAD3 signaling.…”