Department of Pathology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, U.S.A.
Department of Anatomy and Embryology, Maastricht University, Maastricht, The Netherlands.
Clin Sci (Lond). 2023 Jan 31;137(2):143-148. doi: 10.1042/CS20220776.
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.
RAF/MEK/ERK1/2 信号级联反应已被牵涉到某些 Gq 偶联受体下游的病理性心肌肥厚中。RAF 激酶家族由三种同工型（ARAF、BRAF 和 CRAF）组成，直到最近，心脏中关于该信号通路的大多数研究都集中在 RAF1（CRAF）上。在最近的《临床科学》杂志上，Alharbi 等人利用诱导型心肌细胞靶向敲除小鼠模型，分别使用血管紧张素 II 和苯肾上腺素 (PE) 输注来定义 BRAF 在病理性和生理性肥大中的作用。他们报告说，BRAF 的缺失减弱了病理性心肌肥厚和间质纤维化。BRAF 敲除降低了雄性小鼠的心脏功能和 PE 诱导的心肌纤维化，但对心脏收缩力没有影响。相比之下，BRAF 的缺失减弱了雌性小鼠的生理性肥大，但对纤维化或收缩力没有影响。这些观察结果扩展了该研究小组以前的研究结果，即在心脏中表达诱导型 BRAF 激活突变的后果以及通过利用“RAF 悖论”增强 RAF/MEK/ERK1/2 信号的益处。需要进一步的研究来更好地定义 BRAF 在由于高血压施加的生物力学刺激导致心脏慢性应激条件下的作用。此外，BRAF 的作用及其在显性心力衰竭中的激活仍有待确定。然而，新发现强调了其他信号事件的潜在重要性，这些事件可能与 RAF1 或 ERK1/2 激活有关，以性别和上下文依赖的方式塑造 BRAF 信号。
