Heart failure impairs the mechanotransduction properties of human cardiac pericytes. (February 2021)

• Record Type: Journal Article
• Authors: Rolle, Irene Giulia; Crivellari, Ilaria; Zanello, Andrea; Mazzega, Elisa; Dalla, Emiliano; Bulfoni, Michela; Avolio, Elisa; Battistella, Alice; Lazzarino, Marco; Cellot, Alice; Cervellin, Celeste; Sponga, Sandro; Livi, Ugolino; Finato, Nicoletta; Sinagra, Gianfranco; Aleksova, Aneta; Cesselli, Daniela; Beltrami, Antonio Paolo
• Is Part Of: Journal of molecular and cellular cardiology. Volume 151(2021)
• Page Start: 15
• Page End: 30
• Publication Date: 2021-02
• Subjects: Heart failure -- Human pathophysiology -- Pericyte -- Mechano-transduction -- Angiogenesis; AFM atomic force microscopy -- BrdU 5-bromo-2′-deoxyuridine. -- CAS Crk-associated substrate. -- CAV-1 Caveolin-1. -- CMD coronary microcirculation disease. -- CTGF Cellular Communication Network Factor 2. -- CYR61 Cellular Communication Network Factor 1. -- D-Pc donor-heart derived cardiac pericytes. -- DDAH1 Dimethylarginine Dimethylaminohydrolase 1. -- DEG differentially expressed genes. -- DIAPH3 Diaphanous Related Formin 3. -- E-Pc explanted-heart derived cardiac pericytes. -- ERK extracellular signal-regulated kinases. -- FAK focal adhesion kinase. -- GAPDH Glyceraldehyde-3-Phosphate Dehydrogenase. -- GATA4 GATA Binding Protein 4. -- HAND2 Heart And Neural Crest Derivatives Expressed 2. -- IHD ischemic heart disease. -- LATS Large tumor suppressor. -- LPA lysophosphatidic acid. -- LPAR Lysophosphatidic Acid Receptor. -- MAPK mitogen-activated protein kinase. -- MEK Mitogen-activated protein kinase kinase. -- MRTF Myocardin-Related Transcription Factors. -- MST Mammalian Sterile20-like. -- NG2 Chondroitin sulfate proteoglycan 4. -- NMII non-muscle myosin. -- Pc pericyte. -- PDGFR platelet derived growth factor receptor. -- RHO Ras homolog family member. -- ROCK Rho-associated protein Kinase. -- SRF serum response factor. -- TAZ transcriptional coactivator with PDZ-binding motif. -- TBX18 T-box 18. -- TEAD TEA domain transcription factor. -- TF transcription factor. -- β-TRCP beta-transducin repeat containing E3 ubiquitin protein ligase. -- WTIP WT1 Interacting Protein. -- YAP Yes-associated protein.; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2020.10.016
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: The prominent impact that coronary microcirculation disease (CMD) exerts on heart failure symptoms and prognosis, even in the presence of macrovascular atherosclerosis, has been recently acknowledged. Experimental delivery of pericytes in non-revascularized myocardial infarction improves cardiac function by stimulating angiogenesis and myocardial perfusion. Aim of this work is to verify if pericytes (Pc) residing in ischemic failing human hearts display altered mechano-transduction properties and to assess which alterations of the mechano-sensing machinery are associated with the observed impaired response to mechanical cues. Results: Microvascular rarefaction and defects of YAP/TAZ activation characterize failing human hearts. Although both donor (D-) and explanted ( E -) heart derived cardiac Pc support angiogenesis, D-Pc exert this effect significantly better than E-Pc. The latter are characterized by reduced focal adhesion density, decreased activation of the focal adhesion kinase (FAK)/ Crk-associated substrate (CAS) pathway, low expression of caveolin-1, and defective transduction of extracellular stiffness into cytoskeletal stiffening, together with an impaired response to both fibronectin and lysophosphatidic acid. Importantly, Mitogen-activated protein kinase kinase inhibition restores YAP/TAZ nuclear translocation. Conclusion: Heart failure impairs Pc mechano-transduction properties, but this defect could be reversed pharmacologically. Graphical abstract: Unlabelled Image Highlights: End-stage failing ischemic human hearts show microvascular rarefaction. The proangiogenic function of cardiac pericytes is partially exhausted in heart failure. YAP/TAZ are mechanosensitive, pro-angiogenic co-transcriptional regulators. YAP/TAZ nuclear shuttling is reduced in failing hearts-derived cardiac pericytes. This defect could be reversed by pharmacologically inhibiting the MEK/ERK pathway.