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Page 10 of 16 Thirugnanam et al. Vessel Plus 2020;4:26 I http://dx.doi.org/10.20517/2574-1209.2020.18

Figure 4. Important functions of SNRK. The important function of SNRK in various signaling paradigms, and consequence associated
with that in respective tissues is depicted. The arrows indicate activation (black) and inhibition (red). SNRK: sucrose nonfermenting
1-related kinase

therapeutic approaches that support SNRK agonist development is preferred. Further, SNRK’s role at the
interface of inflammation and metabolism will benefit conditions such as heart failure or diabetes. We
hypothesize that molecules such as SNRK that work at interfaces of inflammation-metabolism will help
reduce the progression of the disease. In addition, SNRK’s ability to suppress inflammation in multiple
systems, such as cardiac, adipose, and renal, opens avenues for therapeutic development in these organ
systems.

SNRK in heart failure
Progressive heart failure (HF) is a chronic condition, and current therapies targeting HF are insufficient.
HF is a leading cause of morbidity and is associated with increasing mortality rate worldwide. HF is often
accompanied with significant perturbations in energy metabolism that can affect both cardiac energy
[83]
supply and efficiency . HF is also associated with several underlying comorbidities including dilated
cardiomyopathy, myocardial infarction, hypertension, and myocarditis. Metabolic changes or dysfunctions
in cardiac tissue are one of the main reasons for HF progression. Prolonged exposure of metabolic stress in
the heart decreases its functional ability, especially by reducing mitochondrial function, which is the main
energy generating source in the heart. Mitochondrial dysfunction appears to be a vital target for direct
[84]
intervention to improve cardiac function because it primarily uses fatty acids for ATP production . SNRK
is involved in the regulation of the mitochondrial substrate usage and oxygen consumption to maintain
[16]
cardiac energy and functioning . Progressive HF reduces free fatty acid breakdown resulting in less ATP
production, more inflammation, and increased fibrosis. SNRK in CMs regulates cardiac energy homeostasis
[15]
by maintaining FAO [Figure 4]. Loss of functionally active SNRK in CMs makes the heart vulnerable
and the mice succumb in approximately 9 months. Any additional stress such as angiotensin II (Ang II)
accelerates HF and the mice dies in two weeks post Ang II infusion. Cardiac functional parameters are
[14]
severely compromised with upregulation of inflammation and fibrosis markers in the heart tissue. HF is
typically associated with cardiac remodeling where inflammation and fibrosis are thought to play crucial
[60]
roles . These studies suggest that maintaining SNRK function in CMs is key to preventing HF. In the
[85]
heart, in addition to CMs, ECs are also present in higher numbers than previously thought . Interestingly,
when SNRK was deleted in ECs, the hearts from these mice did not show cardiac function deficits in wild
type state or in Ang II-induced state. As mentioned earlier, the NF-κB pathway was activated in these
[14]
hearts [Figure 4], but no fibrosis was observed . These studies suggest an overriding role for SNRK in
CMs and its compensation of functional defects elicited by other cell types in the heart. Further, SNRK in
CM keeps inflammation and fibrosis under check which allows the heart to continue its function. These
studies suggest important concepts that require more investigation as it relates to SNRK’s role in HF, which