Development of a novel therapeutic approach to cardiac hypertrophy and heart failure

  • Carla De Villiers

Student thesis: Phd

Abstract

Chronic heart failure is a serious, progressive pathology with a rising prevalence and a mortality rate that has not improved in several decades. A new potential treatment strategy is in the targeting of pathological cardiac hypertrophy, which has been demonstrated to be required for the progression of heart failure to occur. PMCA4 has emerged as a promising target to inhibit hypertrophy; knockout or inhibition of PMCA4 has been demonstrated to prevent and reverse heart failure in vivo. Several novel small molecule inhibitors have thus been identified for development as antihypertrophic agents for the treatment of pathological hypertrophy and heart failure. Two of these compounds; C17 and C20, were demonstrated in this project to protect both H9C2 and neonatal rat cardiomyocyte (NRCM) cells from phenylephrine (PE) - induced hypertrophy at concentrations from 10μM to 1μm. These effects were also seen from indirect treatment of H9C2 cells using a model of fibroblast paracrine signalling, suggesting a multi-pathway mode of action. Evidence suggests that the Wnt pathway is involved; treatment with C17 or C20 resulted in a 2.5-fold increase in expression of Wnt inhibitor sFRP2, and prevented a PE-induced increase in Wnt promoter TCF4. A novel mutant mouse line was also investigated, where a mutation rendered PMCA4 as ATPase-inactive, mimicking the pharmacological action of the novel compounds. These mice showed a significant protection from the hypertrophic response to transverse aortic constriction (TAC), with significant differences seen between wild-type TAC and mutant TAC mice for mRNA expression of hypertrophic markers ANP, BNP and GATA4, as well as for cell size and fibrosis. The mutant TAC mice showed increased inhibition of Wnt pathway signalling, with a 4-fold increase in IGFBP5 and a 10-fold increase in sFRP2 mRNA expression levels, as well as showing a 4- fold increase in expression of nNOS. To conclude, this project has demonstrated firstly that the novel small molecule compounds C17 and C20 have anti-hypertrophic properties in vitro, and secondly that the novel PMCA4 ATPase-dead mouse line shows protection from the hypertrophic effects of pressure overload, and has implicated the Wnt and nNOS signalling pathways as being involved.
Date of Award1 Aug 2020
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorElizabeth Cartwright (Supervisor) & Delvac Oceandy (Supervisor)

Keywords

  • Wnt
  • Heart failure
  • Hypertrophy
  • PMCA4
  • TAC

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