C1q/Tumor Necrosis Factor-Related Protein 9 Protects against Acute Myocardial Injury through an Adiponectin Receptor I-AMPK-Dependent Mechanism

Abstract

Obesity is a risk factor for cardiovascular disease. C1q/tumor necrosis factor-related protein 9 (CTRP9) is an adipokine that is downregulated by obesity. We investigated the role of CTRP9 in cardiac injury with loss-of-function genetic manipulations and defined the receptor-mediated signaling pathway downstream of this adipokine. CTRP9-knockout (CTRP9-KO) mice at the age of 12 weeks were indistinguishable from wild-type (WT) mice under basal conditions. CTRP9-KO mice had exacerbated contractile left ventricle dysfunction following intraperitoneal injection of lipopolysaccharide (LPS) compared to WT mice. Administration of LPS to CTRP9-KO mice also resulted in increased expression of proinflammatory cytokines and oxidative stress markers in the heart compared to WT mice. Likewise, CTRP9-KO mice showed increased myocardial infarct size and elevated expression of inflammatory mediators in ischemic heart following ischemia and reperfusion compared to WT mice. Treatment of cardiac myocytes with CTRP9 protein led to suppression of LPS-induced expression of proinflammatory genes, which was reversed by blockade of AMPK or ablation of adiponectin receptor I (AdipoR1). Systemic delivery of CTRP9 attenuated LPS-induced cardiac dysfunction in WT mice but not in muscle-specific transgenic mice expressing dominant-negative mutant form of AMPK or in AdipoR1-knockout mice. CTRP9 protects against acute cardiac damage in response to pathological stimuli by suppressing inflammatory reactions through AdipoR1/ AMPK-dependent mechanisms.O besity causes the progression of various cardiovascular disorders, including ischemic heart disease (1, 2). Adipose tissue functions as an endocrine organ by producing various bioactive secreted proteins, also known as adipokines, that can directly affect the nearby or remote tissues (3). Most adipokines promote obese complications with proinflammatory properties. In contrast, a few numbers of adipokines such as adiponectin are downregulated in obese states, and these factors typically exert salutary actions on obesity-linked cardiovascular disorders (3, 4).C1q/tumor necrosis factor-related protein families (CTRPs) are conserved paralogs of adiponectin that contain collagen-like and globular C1q-like domains (5). CTRP9 has the highest amino acid identity to adiponectin among CTRPs (6). Like adiponectin, CTRP9 is abundantly expressed in adipose tissue. Plasma CTRP9 levels are reduced in diet-induced or leptin-deficient obese mice (6). Clinically, CTRP9 levels associate negatively with visceral fat adiposity and positively with favorable glucose or metabolic phenotypes (7).Several experimental studies demonstrated that CTRP9 acts as an adipokine that modulates metabolic and cardiovascular function. Systemic delivery of CTRP9 lowers glucose levels in obese mice (6). Transgenic overexpression of CTRP9 is protective against diet-induced obesity and glucose intolerance (8), whereas CTRP9-deficiency exacerbates insulin resistance and hepatic steatosis (9). These results suggest that CTRP9 plays a physiolo...

C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure

“…During ischemic injury and proinflammatory stimulation, CTRP9 promotes activation of AMPK and PKA, and both molecules contribute to the protective role of CTRP9 under these circumstances. 14,17,18 During pressure overload, in contrast, we did not find evidence for differential activation of cardiac AMPK or PKA (measured as BAD Ser155 phosphorylation) in response to deletion or overexpression of CTRP9. Instead, we observed enhanced activation of ERK5 during stimulation of isolated cardiomyocytes with recombinant CTRP9 and cardiac AAV-CTRP9 treatment, while in CTRP9 KO mice the induction of ERK5 protein levels in response to pressure overload was markedly blunted compared with what is seen in WT mice.…”

“…10,14,15,18 It was demonstrated in these studies that CTRP9 reduces infarct size (by inhibiting cell death) after ischemia/reperfusion injury and that it inhibits adverse remodeling after myocardial infarction. 14,17,18 Although the different disease models per se might play the biggest role to explain these diverse CTRP9 effects, it is possible that in particular pathologically increased endogenous CTRP9 levels (like we observe in mice early after TAC and in hypertrophic human heart disease) are harmful. One should also consider that the protective effects of CTRP9 administration on cardiac remodeling and survival after myocardial infarction were inferred from administration of recombinant globular CTRP9 (lacking large parts at the N-terminal domain), …”

“…16 With regard to its local function in the heart, CTRP9 was to date reported as cell survival molecule, preventing cardiomyocyte death during ischemia/reperfusion injury and in remodeling after experimental myocardial infarction through binding of the adiponectin receptor 1 (AdipoR1), activation of the AMP-dependent kinase (AMPK), and the protein kinase A (PKA). 14,17,18 We demonstrate here a maladaptive role for CTRP9 during cardiac pressure overload, where CTRP9 becomes upregulated in the heart and serum and drives cardiac hypertrophy by a previously unrecognized ERK5 (extracellular signal-regulated kinase 5)-GATA4 signaling axis.…”

Protective Roles of Adipocytokines and Myokines in Cardiovascular Disease

“…CTRP9 also ameliorates left ventricular dysfunction in a mouse model of endotoxemia. 17 In vitro studies showed that CTRP9 attenuates apoptotic activity and inflammatory reaction in cardiac myocytes. 10, 17 The anti-apoptotic and anti-inflammatory effects of CTRP9 in cardiac myocytes are mediated, at least in part, through its ability to promote the AMPK or cyclic AMP signaling pathway.…”

“…17 In vitro studies showed that CTRP9 attenuates apoptotic activity and inflammatory reaction in cardiac myocytes. 10, 17 The anti-apoptotic and anti-inflammatory effects of CTRP9 in cardiac myocytes are mediated, at least in part, through its ability to promote the AMPK or cyclic AMP signaling pathway. Moreover, CTRP9 improves adverse cardiac remodeling in mice following MI through the PKA-dependent pathway.…”