Central role for BRAF in cardiac hypertrophy: rethinking the pathological–physiological divide. Issue 2 (18th January 2023)

• Record Type: Journal Article
• Authors: Altara, Raffaele; Booz, George W.
• Is Part Of: Clinical science. Volume 137:Issue 2(2023)
• Page Start: 143
• Page End: 148
• Publication Date: 2023-01-18
• Subjects: Cardiac remodeling -- Extracellular signal-regulated MAP kinases -- Fibrosis -- Myocardial contractility -- RAF kinases; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20220776
• Languages: English
• ISSNs: 0143-5221

Abstract

Abstract: The RAF/MEK/ERK1/2 signaling cascade has been implicated in pathological cardiac hypertrophy downstream of some Gq-coupled receptors. The RAF family of kinases consists of three isoforms (ARAF, BRAF, and CRAF) and until recently most studies on this signaling pathway in the heart have focused on RAF1 (CRAF). In a recent issue of Clinical Science, Alharbi et al. utilized an inducible cardiac myocyte targeted knockout mouse model to define the role of BRAF in pathological versus physiological hypertrophy using angiotensin II and phenylephrine (PE) infusion, respectively. They reported that loss of BRAF attenuated both pathological cardiac hypertrophy and interstitial fibrosis. BRAF knockout decreased cardiac function with PE in male mice and enhanced both interstitial and perivascular cardiac fibrosis but had no effect on hypertrophy. In contrast, loss of BRAF attenuated physiological hypertrophy in female mice but had no effect on fibrosis or contractility. These observations extend those previously made by this group assessing the consequences of expressing an inducible activating mutant of BRAF in the heart and the benefit of enhancing RAF/MEK/ERK1/2 signaling by exploiting the 'RAF paradox'. Additional studies are needed to better define the role of BRAF under conditions reflective of chronic stress on the heart due to the biomechanical stimulation exerted by hypertension. In addition, the role of BRAF and its activation in overt heart failure remains to be established. Nevertheless, the new findings highlight the potential importance of additional signaling events, perhaps related to RAF1 or ERK1/2 activation, in shaping BRAF signaling in a sex- and context-dependent manner.