Regression of pathological cardiac hypertrophy: Signaling pathways and therapeutic targets

Abstract

Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming.

Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction

“…TRAF3IP2 Overexpression Results in Cardiac Fibrosis-Pathological hypertrophy is associated with a fibrotic response (22), with remodeling of the extracellular matrix playing a key role in its development and progression. The key structural proteins involved in cardiac fibrosis are collagens type 1␣1 (ColI␣1) and type III␣1 (ColIII␣1).…”

Angiogenesis and Cardiac Hypertrophy

“…64 On the basis of these experimental and clinical observations, we found that the therapeutic myocardial angiogenesis is emerging as a promising approach for the prevention and treatment of heart failure. 65 Several strategies to enhance myocardial angiogenesis have been investigated, including delivery of angiogenic genes or growth factors. The candidate angiogenic factors include VEGF-A, [66][67][68][69] 69,82 and porcine 83 models of MI.…”

Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

“…Copper has been accredited with playing a decisive role in the progression of cardiac diseases through the regulation of HIF-1-targeted angiogenic genes, e.g. VEGF (reviewed by Hou and Kang [281]), so much so that dietary copper replenishment has been envisioned as a promising strategy to reverse the myocardial damage deriving from ischaemia [282]. The use of rat cardiac explants demonstrated that an extended experimental ischaemia leads to an extensive cardiac copper loss and functional damage [283,284].…”