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Page 6 of 16 Thirugnanam et al. Vessel Plus 2020;4:26 I http://dx.doi.org/10.20517/2574-1209.2020.18

Figure 3. SNRK in cardiac metabolism. The role of SNRK in various metabolic pathways involved in cardiac functioning is depicted.
SNRK: sucrose nonfermenting 1-related kinase

strongly on ATP generation, and impairments in this process can rapidly induce contractile dysfunction.
Of the ATP generated in the adult heart, 70% to 90% is produced by the oxidation of fatty acids (or FAO).
The remaining 10% to 30% comes from the oxidation of glucose and lactate, as well as small amounts of
ketone bodies and certain amino acids [45,46] . Because Snrk global KO mice die at or before birth, studying
SNRK function in adult requires conditional deletion of SNRK in cardiac tissue using the CRE-LoxP
system. Cardiomyocyte-specific (myh6-CRE) Snrk KO mice (Snrk cmcKO) show cardiac functional deficits
[15]
at 6 months and die at 9 months. No neonatal lethality was observed in these mice . Neonate hearts from
the Snrk cmcKO mice showed higher ORO retention and no change in pACC-pAMPK signaling pathway.
However, adult Snrk cmcKO hearts at 6 months showed no change in ORO but showed higher pACC
(unpublished data) levels. Thus, the switch in energy source for the heart from glucose in neonates to
fatty acids in adults may partly reflect SNRK’s role at these time points. In terms of cell type, where SNRK
function is critical in the heart, there is little doubt that SNRK-CM function is dominant. This is supported
by the following evidence: (1) Snrk cmcKO show profound cardiac functional deficits at 6 months, die at
9 months, and when stressed by Angiotensin II (Ang II) at 4 months, they show cardiac function deficits
within 14 days and die; (2) Snrk endothelial (TIE2) cell conditional KO (Snrk ecKO) do not show cardiac
functional deficits at 6 months, are alive, and when stressed with Ang II at 4 months do not show cardiac
functional deficits; and (3) SNRK knockdown cardiomyocytes in vitro show metabolic deficits, and NMR
(nuclear magnetic resonance)-based metabolomic analysis revealed SNRK is essential for alanine, aspartate,
and glutamate metabolism [Figure 3] as well as TCA cycle metabolism and it also regulates metabolites
[47]
involved in lipid synthesis such as glycerol . It is also noteworthy that pAMPK-pACC levels were
significantly altered in Snrk ecKO neonate hearts and also in adult hearts (unpublished data). But, despite
these alterations, the SNRK in CMs seem to compensate for cardiac function, and thus prevents functional
deficits.

As for the targets of SNRK that are involved in cardiac function, we had previously reported that ROCK
was a putative SNRK substrate in CMs [Figure 2], and showed that Fasudil (ROCK inhibitor) can rescue