Sucrose non-fermenting related kinase regulates cardiomyocyte protection during cardiac stress

Angiotensin II (Ang II), the key effector of the renin-angiotensin system (RAS) promotes the development of Dilated Cardiomyopathy (DCM), which ultimately leads to heart failure (HF). Previously, our lab has reported that a serine threonine kinase, Sucrose nonfermenting 1-related kinase (SNRK), a member of AMP-activated protein kinase (AMPK) family is critical for cardiac metabolism, and specific loss of SNRK in cardiomyocytes results in DCM. Thus, we hypothesize that, SNRK is involved in maintaining cardiac homeostasis and Ang II exacerbates cardiac dysfunction in cardiomyocyte-specific SNRK knockout mice (SNRK-CKO). To investigate this hypothesis, we performed ECHO on 4 months adult SNRK-CKO mice with and without Ang II, and found that most cardiac function parameters were compromised, followed by death in 14 days. These cardiac function defects were not observed in Ang II-infused SNRK-endothelial (EC) KO mice. We next investigated signaling pathways previously implicated in cardiac dysfunction. Indeed, upon stimulation with Ang II, the heart tissue shows downregulation of pERK and pJNK proteins and upregulation of pAKT protein. In contrast, in SNRK-ECKO, pERK and pJNK proteins were upregulated and pAKT protein was downregulated. Because pAKT, is known to increase inflammatory signaling pathways, in particular IKK-NF-κB, we investigated the IKK-NF-κB signaling in heart lysates from SNRK-CKO and SNRK-ECKO mice. Interestingly, we found upregulation of proinflammatory markers such as IL-6, TNFα and p65 NF-κB and downregulation of anti-inflammatory IL-10 in SNRK-CKO hearts only. This increase in inflammatory signaling is often followed by fibrosis, which was observed via Sirus Red staining for collagen accumulation in Ang II-infused SNRK-CKO hearts. At present, we are investigating the inflammatory and signaling pathways associated with lentivirus-mediated knockdown of SNRK in HL-1 cardiomyocytes in vitro. Overall, these results suggest that SNRK could be a potential target in regulating inflammatory mechanisms, which exerts cardioprotective effect in the heart.