Commentary Central role for BRAF in cardiac hypertrophy : rethinking the pathological-physiological divide

The RAF/MEK/ERK1/2 signaling cascade has been implicated in pathological cardiac hy-pertrophy 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 de-fine 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 car-diac fibrosis but had no effect on hypertrophy. In contrast, loss of BRAF attenuated phys-iological 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

Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects

Diabetes is a global epidemic and a leading cause of death with more than 422 million patients worldwide out of whom around 392 million alone suffer from type 2 diabetes (T2D). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel and effective drugs in managing glycemia of T2D patients. These inhibitors gained recent clinical and basic research attention due to their clinically observed cardiovascular protective effects. Although interest in the study of various SGLT isoforms and the effect of their inhibition on cardiovascular function extends over the past 20 years, an explanation of the effects observed clinically based on available experimental data is not forthcoming. The remarkable reduction in cardiovascular (CV) mortality (38%), major CV events (14%), hospitalization for heart failure (35%), and death from any cause (32%) observed over a period of 2.6 years in patients with T2D and high CV risk in the EMPA-REG OUTCOME trial involving the SGLT2 inhibitor empagliflozin (Empa) have raised the possibility that potential novel, more specific mechanisms of SGLT2 inhibition synergize with the known modest systemic improvements, such as glycemic, body weight, diuresis, and blood pressure control. Multiple studies investigated the direct impact of SGLT2i on the cardiovascular system with limited findings and the pathophysiological role of SGLTs in the heart. The direct impact of SGLT2i on cardiac homeostasis remains controversial, especially that SGLT1 isoform is the only form expressed in the capillaries and myocardium of human and rodent hearts. The direct impact of SGLT2i on the cardiovascular system along with potential lines of future research is summarized in this review. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.Funding Source This work was supported by grants from the American University of Beirut (Seed grant #100410, MPP grant #320145) to FAZ

Caloric Restriction Rejuvenates Skeletal Muscle Growth in Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a major clinical problem, with limited treatments. HFpEF is characterized by a distinct, but poorly understood, skeletal muscle pathology, which could offer an alternative therapeutic target. In a rat model, we identified impaired myonuclear accretion as a mechanism for low myofiber growth in HFpEF following resistance exercise. Acute caloric restriction rescued skeletal muscle pathology in HFpEF, whereas cardiac therapies had no effect. Mechanisms regulating myonuclear accretion were dysregulated in patients with HFpEF. Overall, these findings may have widespread implications in HFpEF, indicating combined dietary with exercise interventions as a beneficial approach to overcome skeletal muscle pathology