Blockage of DCLK1 in cardiomyocytes suppresses myocardial inflammation and alleviates diabetic cardiomyopathy in streptozotocin-induced diabetic mice

Diabetic cardiomyopathy (DCM) is a pathophysiological condition triggered by diabetes mellitus and can lead to heart failure. Doublecortin-like kinase protein 1 (DCLK1) is a multifunctional protein kinase involved in the regulation of cell proliferation, differentiation, survival, and migration. Current studies on DCLK1 mainly focus on cancer development; however, its role in non-tumor diseases such as DCM is yet to be deciphered. Our analysis revealed that DCLK1 was upregulated in cardiomyocytes of streptozotocin (STZ)-induced type 1 diabetic mouse, suggesting a correlation between DCLK1 and DCM progression. It was further demonstrated that either cardiomyocyte-specific DCLK1 knockout or pharmacological DCLK1 inhibitor DCLK1-IN-1 significantly alleviated cardiac hypertrophy and fibrosis in STZ-induced diabetic mice. RNA-seq analysis of heart tissues revealed that DCLK1 regulated the nuclear factor kappa B (NF-κB)-mediated inflammatory response in DCM. In vitro, DCLK1 activated NF-κB and the inflammatory response by inducing the IKKβ phosphorylation in high-concentration glucose (HG)-challenged cardiomyocytes. DCLK1-IN-1 also prevented HG-induced IKKβ/NF-κB activation and inflammatory injuries in cardiomyocytes. In conclusion, this study highlights the novel role of cardiomyocyte DCLK1 in regulating IKKβ/NF-κB, which aggravates inflammation to promote the pathogenesis of DCM. DCLK1 may serve as a new target for DCM treatment. [Display omitted] •DCLK1 is upregulated in the heart tissues of STZ-induced diabetic mice.•Either DCLK1 deletion in cardiomyocytes or pharmacological inhibition of DCLK1 attenuated DCM in diabetic mice.•DCLK1 regulates NF-κB pathway to aggravate inflammation in cardiomyocytes.•DCLK1 could be a novel therapeutic target for the treatment of inflammatory DCM.