Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload

Abstract

The cardiac pathological response to sustained pressure overload involves myocyte hypertrophy and dysfunction along with interstitial changes such as fibrosis and reduced capillary density. These changes are orchestrated by mechanical forces and factors secreted between cells. One such secreted factor is TGF-β, which is generated by and interacts with multiple cell types. Here we have shown that TGF-β suppression in cardiomyocytes was required to protect against maladaptive remodeling and involved noncanonical (non-Smad-related) signaling. Mouse hearts subjected to pressure overload and treated with a TGF-β-neutralizing Ab had suppressed Smad activation in the interstitium but not in myocytes, and noncanonical (TGF-β-activated kinase 1 [TAK1]) activation remained. Although fibrosis was greatly reduced, chamber dysfunction and dilation persisted. Induced myocyte knockdown of TGF-β type 2 receptor (TβR2) blocked all maladaptive responses, inhibiting myocyte and interstitial Smad and TAK1. Myocyte knockdown of TβR1 suppressed myocyte but not interstitial Smad, nor TAK1, modestly reducing fibrosis without improving chamber function or hypertrophy. Only TβR2 knockdown preserved capillary density after pressure overload, enhancing BMP7, a regulator of the endothelial-mesenchymal transition. BMP7 enhancement also was coupled to TAK1 suppression. Thus, myocyte targeting is required to modulate TGF-β in hearts subjected to pressure overload, with noncanonical pathways predominantly affecting the maladaptive hypertrophy/dysfunction.

Angiotensin II-induced cardiomyocyte hypertrophy in vitro is TAK1-dependent and Smad2/3-independent

“…These data indicate that AngII and TGFb1 promote a hypertrophic response, which is TAK1-dependent and is consistent with in vivo data showing the importance of TAK1 in cardiac hypertrophy. 9,10,22 Our data also suggest that the previously reported TGFb1-dependent induction of cardiac hypertrophy by Ang II in vivo would have required TAK1 activity, but not Smad2/3 signalling. 6 We found that reduction of Smad2/3 proteins did not inhibit the hypertrophic response, suggesting cardiac hypertrophy is Smad2/3 independent.…”

“…A number of studies have pointed to the importance of TAK1 signalling in the hypertrophic response. 9,10,22 We therefore wished to investigate whether either Smad2/3 or TAK1 or both were required for hypertrophic responses in cardiomyocytes in culture. SiRNA oligonucleotide transfection was first used to knockdown the expression of Smad2/3, and scrambled oligos were used to control for non-specific effects of transfection.…”

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

“…2 0 0 7 ) , thromhospondin-1 (Thbs1) (Lawler 2002), Thbs2 (Volpert et al 1995), the potent anti-angiogenic chemokine platelet factor 4 (Pf4) (Bikfalvi 2004); vasohibin-1 (Vash1), which is a newly recognized (Takano et al 2014), Adamts1 ("a disintegrin and metalloproteinase with thrombospondin motifs 1"), which inhibits angiogenesis (Lee et al 2006) by suppressing endothelial cell proliferation; Col18a1, whose expression level impacts endostatin signaling and endothelial angiogenic capacity (Li and Olsen 2004) (endostatin, a potent inhibitor of angiogenesis, is a 20-kDa C-terminal fragment derived from type XVIII collagen); semaphorin-3F (Sema3f) (Ungvari et al 2011b;Frisbee et al 2007); tenomodulin (Tnmd) (Oshima et al 2003); brainspecific angiogenesis inhibitor 1 (Bai1; also known as adhesion G protein-coupled receptor B1 [ADGRB1]) (Nishimori et al 1997); chromogranin A (Chga), which encodes the precursor to several angiogenesis inhibitor peptides including vasostatin-1 and vasostatin-2 (Helle and Corti 2015) and maspin ("mammary serine protease inhibitor"; encoded by the Serpinb5 gene (Qin and Zhang 2010). Figure 7 shows the expression of Tnfa, whose overproduction has been causally linked to microvascular rarefaction (Frisbee et al 2014); Tgfb1, which regulates multiple aspects of the angiogenic process and contributes to hypertension-induced microvascular rarefaction in the heart (Koitabashi et al 2011); Tgfa; angiogenin (Ang, also known as ribonuclease 5), which is a potent stimulator of angiogenesis and an inhibitor of endothelial apoptosis; Edil3 (EGF-like repeats and discoidin Ilike domains 3), which encodes a glycoprotein secreted by endothelial cells that regulates apoptosis, cell migration (Zhong et al 2003) and induces cerebral angiogenesis in mice (Fan et al 2008); midkine (Mdk, also known as neurite growth-promoting factor 2 or NEGF2), which is a pleiotropic growth factor regulating cell proliferation, cell migration and promoting angiogenesis (Mashour et al 2001 [HB-GAM]), which is a pro-angiogenic growth factor that is structurally related to midkine and whose expression in the adult brain is induced by ischemia; Tymp (thymidine phosphorylase, also known as platelet-derived endothelial cell growth factor [ECGF1], which stimulates endothelial cell proliferation and induces angiogenesis in the brain (Hayashi et al 2007); platelet endothelial cell adhesion molecule (Pecam1; also known as CD31), which confers pro-angiogenic effects (Park et al 2015)<...>…”

Les acteurs moléculaires du remodelage cardiaque pathologique

“…Il faut citer ici les travaux fondateurs de Molkentin et Olson portant sur la voie de signalisation de la calcineurine (CaN) [6] (Figure 2). Cette phosphatase, initialement identifiée dans les lymphocytes, est responsable de la translocation nucléaire du facteur de transcription NFAT (nuclear factor of activated T-cells) qui peut ensuite activer ses [9]. Ces deux exemples illustrent le fait que le caractère pathologique du remodelage ne se comprend in fine qu'avec l'analyse de l'ensemble des aspects du remodelage et de leurs conséquences fonctionnelles sur le coeur.…”