Diabetes is a major risk factor for cardiovascular disease. The diabetic heart undergoes structural and functional alterations that often progress to heart failure (HF) that affects approximately 14.5% of individuals with type 1 diabetes and 35% of those with type 2 diabetes mellitus.1,2 Currently, there are no approved therapies specifically targeting diabetic heart injury. A deeper understanding of the underlying mechanisms is urgently needed to facilitate the development of novel therapeutic strategies.

G protein-coupled receptors (GPCRs) represent one of the largest superfamilies of transmembrane receptors, whose activity is tightly regulated by GPCR kinases (GRKs). Among the seven isoforms, GRK2, 3, and 5 are predominant in the heart, with GRK3 expression restricted to cardiomyocytes.3 Unlike the well-characterized GRK2 and GRK5, GRK3 remains less investigated in physiological and pathological settings.

In the current paper,4 Gao et al. uncover a novel role for GRK3 in diabetic heart injury. Specifically, the authors demonstrate that GRK3 is the predominant GRK upregulated in response to hyperglycemia in human hearts and in cardiac tissues from mouse models of type 1 (db/db mice) and type 2 (high-fat diet [HFD]/streptozotocin [STZ]-treated mice) diabetes. DNA pulldown and mass spectrometry identified Yin-Yang 1 (YY1) as a repressor of Grk3 transcription under euglycemia; hyperglycemia reduces YY1, enhancing Grk3 expression. 
The authors generated a transgenic mouse model with cardiomyocyte-specific inactivation of GRK3. Diabetic mice deleted for cardiac GRK3 show decreased cardiac remodeling with improved cardiac function. Having previously established that cannabinoid receptor 2 (CB2R) exerts protective effects against diabetic heart injury in both humans and mice,5 the authors hypothesized that this GPCR could be a downstream target of GRK3. Consistent with this, cardiac-selective CB2R knockout abolished the cardioprotective effects of GRK3 inhibition in diabetic mouse hearts. Importantly, molecular analyses revealed that GRK3 reduces CB2R expression by promoting β-arrestin 2-dependent CB2R internalization under high-glucose conditions. GRK3 specifically phosphorylated CB2R at serine 335 (S335), thereby facilitating its internalization and ubiquitin-dependent degradation in cardiomyocytes during hyperglycemia.

Finally, having the proof-of-concept that GRK3 inhibition protects the heart from diabetic injury, the authors performed a high-throughput virtual screening to isolate efficient inhibitors of GRK3. They characterize isochlorogenic acid A (ICQA), a compound initially isolated in a variety of teas and vegetables, as an GRK3 inhibitor that prevents cardiac remodelling associated with diabetes. This finding is intriguing from a translational perspective. However, it will be important to assess the potential cardioprotective effects of ICQA in additional mouse models of diabetic cardiomyopathy, particularly those that recapitulate features of human HF with preserved ejection fraction.6

In conclusion, this study puts GRK3 on the map as a driver of diabetic injury to the heart. The molecular mechanism identified is related to GRK3-dependent phosphorylation of CB2R at S335, promoting its internalization and degradation. YY1 binds to the GRK3 promoter, repressing its transcription during euglycemia, while hyperglycemia decreased YY1 and thereby upregulates GRK3 levels. GRK3-targeting compounds may therefore open up to novel therapeutic strategies for diabetic heart injury.