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Cardiomyocyte-specific ADGRF5 mediates cardiac homeostasis via Gαq coupling

ABSTRACT: G-Protein Coupled Receptors (GPCRs) represent one of the most targeted drug classes in the human genome, accounting for greater than 40% of all FDA-approved drugs, including gold-standard heart failure (HF) therapeutics. However, the second-largest family of GPCRs, known as Adhesion GPCRs (aGPCR), have yet to serve as a clinical target despite increasing evidence of their pathophysiological contributions, representing an area of highly unexplored druggable potential. We identified an aGPCR, known as ADGRF5, to be highly expressed in the left ventricle (LV) of C57BL/6, which we also found increases in response to transaortic constriction (TAC) surgery. To determine the impact of ADGRF5 on cardiac parameters normally or during HF, we generated constitutive cardiomyocyte-specific (αMHC-Cre-driven) ADGRF5 knockout mice (CM-ADGRF5-KO), which displayed normal cardiac structure and function at 12 weeks of age, as assessed via echocardiography, gravimetrics and immunohistochemistry. However, over time CM-ADGRF5-KO mice developed worsened cardiac function and remodeling with increased mortality, even in the absence of pathologic insult, suggesting ADGRF5 provides a homeostatic regulatory function in the heart. We assessed changes in cardiac gene expression at 12 weeks of age, a timepoint prior to the onset of the eccentric remodeling on the CM-ADGRF5-KO mice. We identified 58 differentially expressed genes, with 31 downregulated and 27 upregulated.

ORGANISM(S): Mus musculus

PROVIDER: GSE207703 | GEO | 2024/07/01

REPOSITORIES: GEO

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Project description:Background: Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we employed an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown. Methods: We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte-specific HIPK2 knockout (CM-KO) and heterozygous (CM-Het) mice. Heart function was examined by echocardiography and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 (AAV9) carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) were administrated to rescue cardiac dysfunction in CM-KOs. Results: To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in cardiomyocytes leads to cardiac dysfunction—suggesting a causal role in heart failure. Importantly, cardiac dysfunction in HIPK2 KOs developed with advancing age, but not during development. In addition, CM-KO and CM-Het exhibited a gene dose-response relationship of cardiomyocyte HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy compared to non-failing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular cardiomyocytes corroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers, NPPA and NPPB, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired ERK1/2 signaling in HIPK2 deficient hearts. In vivo rescue experiment with AAV9 TnT-MEK1-CA nearly abolished the detrimental phenotype of KOs suggesting that impaired ERK signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-KO hearts. Conclusions: Taken together, these findings suggest that cardiomyocyte HIPK2 is required to maintain normal cardiac function via ERK signaling

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Cardiomyocyte-specific ADGRF5 mediates cardiac homeostasis via Gαq coupling

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