Abstract:Introduction
Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure.
Hypothesis
We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure.
Methods and Results
In patients with advanced heart failure referred for left ventricular (LV) assist device implantation, LV Alk1 mRNA and protein levels were lower than control LV … Show more
“…In a mouse model of scleroderma-like fibrosis due to forced expression of ALK5, activation of a fibrogenic transcriptional program was dependent on Smad1 and Erk1/2, and not on Smad2/3 (Pannu et al, 2007), suggesting that an ALK1/Smad1 pathway may be critically involved in certain fibrotic conditions. In contrast, in other studies, partial loss of ALK1 enhanced fibroblast-mediated matrix synthesis (Muñoz-Félix et al, 2014b), and ALK1 +/− mice exhibited increased fibrosis in experimental models of renal (Muñoz-Félix et al, 2014a) and cardiac (Morine et al, 2017) injury. In the absence of fibroblast-specific targeting experiments, and considering the likely effects of Smad1 on endothelial cells and other cell types, these findings are difficult to interpret.…”
Section: The Molecular Signals Involved In Tgf-β-mediated Fibrosismentioning
TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.
“…In a mouse model of scleroderma-like fibrosis due to forced expression of ALK5, activation of a fibrogenic transcriptional program was dependent on Smad1 and Erk1/2, and not on Smad2/3 (Pannu et al, 2007), suggesting that an ALK1/Smad1 pathway may be critically involved in certain fibrotic conditions. In contrast, in other studies, partial loss of ALK1 enhanced fibroblast-mediated matrix synthesis (Muñoz-Félix et al, 2014b), and ALK1 +/− mice exhibited increased fibrosis in experimental models of renal (Muñoz-Félix et al, 2014a) and cardiac (Morine et al, 2017) injury. In the absence of fibroblast-specific targeting experiments, and considering the likely effects of Smad1 on endothelial cells and other cell types, these findings are difficult to interpret.…”
Section: The Molecular Signals Involved In Tgf-β-mediated Fibrosismentioning
TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.
“…In contrast, the 26G TAC model represents the transition between compensated and decompensated heart failure, with some systolic dysfunction evident, such as reduced preload-recruitable stroke work and cardiac output in addition to perivascular cardiac fibrosis. The 26G TAC model may therefore be especially useful to study cardiac hypertrophy, dysfunction and fibrosis in genetically modified mice with increased susceptibility to mortality 14,29 . In this situation, cardiac pathology is still observed, but the relative high mortality might be avoided.…”
Transverse aortic constriction (TAC) is a well-established model of pressure overload-induced cardiac hypertrophy and failure in mice. The degree of constriction “tightness” dictates the TAC severity and is determined by the gauge (G) of needle used. Though many reports use the TAC model, few studies have directly compared the range of resulting phenotypes. In this study adult male mice were randomized to receive TAC surgery with varying degrees of tightness: mild (25G), moderate (26G) or severe (27G) for 4 weeks, alongside sham-operated controls. Weekly echocardiography and terminal haemodynamic measurements determined cardiac remodelling and function. All TAC models induced significant, severity-dependent left ventricular hypertrophy and diastolic dysfunction compared to sham mice. Mice subjected to 26G TAC additionally exhibited mild systolic dysfunction and cardiac fibrosis, whereas mice in the 27G TAC group had more severe systolic and diastolic dysfunction, severe cardiac fibrosis, and were more likely to display features of heart failure, such as elevated plasma BNP. We also observed renal atrophy in 27G TAC mice, in the absence of renal structural, functional or gene expression changes. 25G, 26G and 27G TAC produced different responses in terms of cardiac structure and function. These distinct phenotypes may be useful in different preclinical settings.
“…6 ), and showed decreased levels of urine sodium and chloride levels in Alk1ΔEC−/− mice. Since urine albuminuria and serum electrolytes did not vary between C5Cre and Alk1ΔEC−-/− mice, changes in sodium and chloride levels in urine may be indicative of vascular hyperpermeability or early cardiac failure, which have been associated with Alk1 loss-of-function 17 , 34 – 36 . Figure 7 Effects of Alk1ΔEC homozygote deletion on renal function.…”
Section: Resultsmentioning
confidence: 98%
“…6), and showed decreased levels of urine sodium and chloride levels in Alk1ΔEC−/− mice. Since urine albuminuria and serum electrolytes did not vary between C5Cre and Alk1ΔEC−-/− mice, changes in sodium and chloride levels in urine may be indicative of vascular hyperpermeability or early cardiac failure, which have been associated with Alk1 loss-of-function 17,[34][35][36] . Even though complete Alk1 deletion did not result in glomerular filtration defects within the time-frame of these experiments, we evaluated whether it could result in early glomerular alterations which could predispose to the development of glomerular dysfunction.…”
Section: Evidence Of Urine Albumin Excretion and Hyperfiltration In Amentioning
Endothelial dysfunction has been shown to play an important role in the pathogenesis of glomerular damage during diabetic kidney disease (DKD). As such, a better understanding of the molecular mechanisms involved in glomerular endothelial dysfunctions could provide novel therapeutic strategies for the prevention of DKD. We have previously shown that Alk1/BMP9 signaling plays an important function to maintain vascular integrity in diabetic animals. As such, we evaluated the effects of Alk1 suppression on glomerular endothelial function in diabetic mice. In the present study, we used mice with conditional heterozygote deletion of Alk1 in the endothelium (Alk1ΔEC) to evaluate the role of Alk1 on kidney function during STZ-induced diabetes. DKD was investigated in diabetic control and Alk1ΔEC mice euthanized eight weeks after the onset of diabetes. We showed that Alk1 expression is reduced in the glomeruli of human DKD patients. While renal function was not altered in Alk1ΔEC non-diabetic mice, we showed that Alk1 haploinsufficiency in the glomerular endothelium leads to microalbuminuria, thickening of the glomerular basement membrane, glomerular apoptosis and podocyte loss in diabetic mice. These data suggest that Alk1 is important for the proper function of glomerular endothelial cells and that decreased Alk1 combined with chronic hyperglycemia can impair renal function.
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