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Page 8 of 16 Thirugnanam et al. Vessel Plus 2020;4:26 I http://dx.doi.org/10.20517/2574-1209.2020.18

degree and duration of the response varies, and this dictates whether the final outcome of the inflammation
will be beneficial or harmful. A prolonged inflammatory response has negative consequences such as
activation of a fibrotic response where excessive and aberrant accumulation of collagenous connective
tissues occurs in the organs that can weaken tissue function, and in some cases, lead to organ failure (e.g.,
chronic hepatitis B) [22,59,60] .

Often, inflammation is associated with fibrosis in cardiac, adipose and renal tissues [8,14,22,61] . Evidence in
recent years point to a strong link between chronic low-grade inflammation in the heart and metabolic
dysregulation [62-64] . In the case of heart failure and cardiac hypertrophy, the progression of inflammation
usually involves a local rise of cytokines in cardiac cells such as CMs, ECs, and fibroblasts and the
activation of the proinflammatory transcription factor nuclear factor NF-κB [14,65,66] . In the cardiac system,
inflammation is often associated with the deposition of collagen, leading to fibrosis in the heart. Removal
of Snrk in CMs increases the phosphorylation of NF-κB p65 and increases proinflammatory cytokine
signaling which is partially mediated through Akt. This suggests that SNRK represses inflammation
signaling in CMs, which when unchecked, progresses to fibrosis and death. However, when Snrk is deleted
in cardiac ECs, these hearts show increases in NF-κB p65 and proinflammatory cytokine signaling, which
does not progress to fibrosis. These data collectively suggest that SNRK in CMs compensates for SNRK
[14]
loss of function in ECs , and also implies crosstalk signaling between CMs and ECs in cardiomyocyte
remodeling.

Healthy adipose tissue is vital for metabolic homeostasis, whereas dysfunctional adipose is a contributing
factor for metabolic disorders such as obesity, type 2 diabetes mellitus, and cardiovascular diseases [67-69] .
SNRK expression is high in the metabolic adipose tissue. In the adipocytes, SNRK protein is localized to
[19]
lysosomes, the site for degradation of large intracellular organelles or assembly of protein aggregates .
Adipocyte-specific SNRK represses inflammation in WAT through the JNK and IKKβ signaling pathways.
Under obesity conditions, the expression level of SNRK is low because of obesity-induced adipose
inflammation and/or lipid toxicity. Removal of SNRK specifically in adipocytes leads to metabolic
disturbances with decreased energy expenditure, higher body weight, and increased insulin resistance [18,19] ,
suggesting that SNRK regulates and controls these metabolic pathways.

In the renal system, SNRK in glomerular ECs binds directly to p65 subunit of NF-κB (activated by Ang II)
to suppress inflammatory signaling. Activated NF-κB plays a critical role in renal damage which occurs as
[22]
a result of unchecked inflammation and fibrosis . These evidences suggest that SNRK acts as a repressor
of inflammation in cardiac, adipose, and renal tissues, all of which are critical for the maintenance of
organismal homeostasis and function.

Role of SNRK in vascular development
During embryonic development, vascular networks permeate the entire body and this conduit is used for
the circulation of metabolites and removal of waste products. The vascular system emerges as one of the
earliest networks in the embryo to support the rapid growth of tissues. The adult vasculature is generally
quiescent but retains the capacity to shift from this dormant state to an expansion and remodeling state.
This occurs during normal physiological conditions such as wound healing or pathological states such as
tumor neovascularization. The differentiation of angioblasts (precursor cells) into ECs and the de novo
formation of a primitive vascular network is called vasculogenesis. After primary vascular plexus is
formed, a second process during development occurs wherein more ECs are generated via a process called
angiogenesis which is the growth of new blood vessels from existing vasculature . Thus, vasculogenesis
[70]
and angiogenesis are the two predominant sequential coordinated processes for blood vessel formation
during development [70,71] .