Abstract
TGF-β regulates tissue fibrosis: TGF-β promotes fibrosis, whereas bone morphogenetic protein (BMP)-7 is antifibrotic. To demonstrate that (i) left ventricular (LV) remodelling after pressure overload is associated with disequilibrium in the signalling mediated by these cytokines, and (ii) BMP-7 exerts beneficial effects on LV remodelling and reverse remodelling. We studied patients with aortic stenosis (AS) and mice subjected to transverse aortic constriction (TAC) and TAC release (de-TAC). LV morphology and function were assessed by echocardiography. LV biopsies were analysed by qPCR, immunoblotting, and histology. Pressure overload reduced BMP-7 and pSmad1/5/8 and increased TGF-β and pSmad2/3 in AS patients and TAC mice. BMP-7 correlated inversely with collagen, fibronectin, and β-MHC expressions, and with hypertrophy and diastolic dysfunction, and directly with the systolic function. Multiple linear regression disclosed BMP-7 and TGF-β as hypertrophy predictors, negative and positive, respectively. BMP-7 prevented TGF-β-elicited hypertrophic program in cardiomyocytes, and Col1A1 promoter activity in NIH-3T3 fibroblasts. The treatment of TAC mice with rBMP-7 attenuated the development of structural damage and dysfunction, and halted ongoing remodelling. The reverse remodelling after pressure overload release was facilitated by rBMP-7, and hampered by disrupting BMP-7 function using a neutralizing antibody or genetic deletion. The disequilibrium between BMP-7 and TGF-β signals plays a relevant role in the LV remodelling response to haemodynamic stress in TAC mice and AS patients. Our observations may provide new important insights aimed at developing novel therapies designed to prevent, halt, or reverse LV pathological remodelling in pressure overload cardiomyopathy.
Highlights
Aortic stenosis (AS) is an age-related valve disorder; it constitutes the most common adult heart valve disease that requires surgery in the Western world and it will keep gaining importance due to the progressive increase in life expectancy in our societies [1]
Our findings in patients with severe AS and in a mouse model of reversible pressure overload raise two important notions: (i) an imbalance between Bone Morphogenetic Protein (BMP)-7 and Transforming Growth Factors (TGF)-β signals could play a major etiopathogenic role in the maladaptive Left ventricular (LV) remodeling under pressure overload; and (ii) strategies to enhance the activity of BMP-7 signaling may have putative therapeutic value to attenuate ongoing myocardial hypertrophy and to favor the reverse remodeling after releasing the LV from the hemodynamic load
TGF-β and BMP-7 belong to the same superfamily, each of these cytokines exhibit a unique signaling pathway through specific Smad proteins that determine some effects that are opposite in each pathway
Summary
Aortic stenosis (AS) is an age-related valve disorder; it constitutes the most common adult heart valve disease that requires surgery in the Western world and it will keep gaining importance due to the progressive increase in life expectancy in our societies [1]. The only effective therapy for symptomatic AS patients is the aortic valve replacement. After releasing the biomechanical stress, the LV undergoes a process of reverse remodeling [4,5]. When the LV structural damage is severe the remodeling process becomes irreversible after surgery, which results in unfavorable short‐ and long‐term outcome of AS patients [4,6,7]. The lack of preventive therapies of myocardial remodeling in AS patients highlights need for new effective drugs to delay the progression of LV structural damage before surgery and to improve and accelerate the reverse remodeling after releasing the hemodynamic stress
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