GRK5‐mediated Exacerbation of Ischemic Heart Failure Involves Cardiac Immune and Inflammatory Responses
Authors: de Lucia Claudio , Grisanti Laurel A. , Borghetti Giulia , Ibetti Jessica , Lucchese Anna Maria , Gao Erhe , Rengo Giuseppe , Houser Steven R. , Tilley Douglas , Koch Walter J. 
Published: June 2021

RATIONALE

Coronary artery disease and subsequent myocardial ischemia (MI) are the most common cause of heart failure (HF) in the US. G protein‐coupled receptor (GPCR) kinase 5 (GRK5) has been shown to be upregulated in failing human myocardium. While the canonical role of GRKs is to desensitize receptors via phosphorylation, GRK5 can also locate to the nucleus of cardiomyocytes where it exerts GPCR‐independent effects that promote maladaptive cardiac hypertrophy after hypertrophic stress. Despite numerous data indicating the importance of GRK5 in hypertrophy, it is still unknown if GRK5 has a role in ischemic heart disease.

OBJECTIVE

In this study, we investigated the critical role that GRK5 plays after myocardial ischemic injury with a novel aspect being the regulation of immune and inflammatory responses including recruitment of immune cells to the injured heart.

METHODS AND RESULTS

Cardiac‐specific GRK5 transgenic mice (Tg‐GRK5) and non‐transgenic littermate (NLC) control mice were subjected to MI. Tg‐GRK5‐HF mice showed decreased cardiac function (both global and segmental contractility), augmented left ventricular diameters/volumes and decreased survival rate compared to NLC‐HF mice. Heart weight (HW) to body weight or to tibia length ratios as well as mRNA expression of all major adverse remodeling‐associated biomarkers (ANF, BNP, b‐MHC) were increased in the TgGRK5‐HF compared to NLC‐HF. Cardiac fibrosis in the border zone (BZ) area as well as mRNA levels of Collagen‐1 (Col‐1), Col‐3, MMP2 and CTGF were higher in TgGRK5‐HF compared to NLC‐HF, strongly suggesting increased adverse remodeling. Cardiac inflammatory cytokines (IL‐6 and IL‐1beta), adhesion molecule (VCAM‐1) and chemokines (CCL2, CCL3, CCL5) were augmented in TgGRK5‐HF compared to NLC‐HF and contribute at least in part to increased immune cell recruitment in the heart. In fact, we found neutrophils/macrophages and T‐lymphocytes (T‐cells) respectively augmented at 4 days and 8 weeks after MI in both BZ and infarct zone. Interestingly, cardiac‐specific GRK2 transgenic mice did not show increased cardiac inflammation and chemokine production after MI when compared to NLC‐HF mice.

CONCLUSIONS

Our study shows that cardiac GRK5 has a detrimental effect during ischemic HF. GRK5 overexpression causes reduced cardiac function and increased immune cell recruitment/inflammation. Further, these results suggest GRK5 as a potential therapeutic target to limit HF development after ischemic injury.

Support or Funding Information

This work was supported by National Institutes of Health (NIH P01 HL091799, NIH R37 HL061690, NIH P01 HL075443 [Project 2]) to W.J.K. and American Heart Association (postdoctoral fellowship 17POST33660942) to C.d.L..

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.