Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis

Abstract

Hepatic JAK2/ARHGEF1/ROCK expression is associated with portal hypertension and decompensation in human cirrhosis. The deletion of Jak2 in myofibroblasts attenuated experimental fibrosis and acute inhibition of JAK2 decreased PP. Thus, JAK2 inhibitors, already in clinical use for other indications, might be a new approach to treat cirrhosis with portal hypertension.

Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis

“…These effects are mediated by upregulated RhoA/Rho-kinase signaling upon liver damage (Trebicka et al, 2007(Trebicka et al, , 2010. Our group has demonstrated several times that the signaling cascade via JAK2, RhoA, and Rho-kinase signaling is upregulated in liver fibrosis and located mainly in myofibroblast-like activated HSC (Zhou et al, 2006;Granzow et al, 2014;Klein et al, 2015). With the current study we show that increased RhoA activity leads to decreased c-SRC activity with progressive HSC activation.…”

“…Besides inhibition of c-SRC, PP2 has been described to have a weak affinity to inhibit other kinases like JAK2 (Hanke et al, 1996), which is an upstream regulator of RhoA activity (Granzow et al, 2014;Klein et al, 2015). However, the doses of PP2 used in our in vitro experiments was very low and much higher doses would be of need to inhibit the JAK2/RhoA axis (Hanke et al, 1996).…”

Hepatic stellate cells as key target in liver fibrosis

“…Angiotensin II, secreted by HSCs, binds to angiotensin II type 1 receptor (AT1R) and promotes liver fibrosis via JAK2, which is associated with portal hypertension [143, 144]. Blocking the renin–angiotensin system by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) such as losartan may be an effective antifibrotic therapy as suggested by experimental and clinical studies [145, 146].…”

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…Further studies may determine whether some of the clinical benefits of statins related to cardiovascular and liver-related mortality in NAFLD [93,94] originate from a direct impact on sinusoidal homeostasis. Additional agents with impact on HSC activation and contractility include mitochondrial antioxidants [95,96], renin-angiotensin system inhibitors [97], and relaxin [98]. Finally, selective Experimental Intestinal decontamination by rifaximin blocks TLR4-mediated activation of HSCs and modulates FXR signaling by changing intestinal bile acid composition associated with reduced fibrosis, angiogenesis, and PVP in experimental PHT [69] beta3 receptor agonists induce relaxation of HSCs via cAMP accumulation and Rho-kinase inhibition with no effect on normal PVP, indicating that these drugs primarily target the dynamic components of IHVR [99,100].…”