Caveolin-3 Nitrative Modification: A Novel Mechanism of Cardiac Insulin Resistance in Pre-Diabetic Animals

Abstract

Rationale: Diabetes-induced myocardial insulin resistance leads to cardiac injury. There is, however, no consensus on the underlying molecular mechanisms. Studies have demonstrated that diabetic hearts are resistant to other cardioprotective interventions, such as adiponectin and preconditioning. In the face of multiple therapeutic interventions, the “universal” resistance suggests the impairment of the requisite molecule(s) involved in broad pro-survival signaling cascades. Caveolin (Cav) sits on cellular membrane and coordinates transmembrane signaling. It remains unknown whether Cav3 contributes to diabetic ischemic heart failure (HF) and impaired cardiac protective signaling. Methods and Results: Mice were fed a normal diet (ND) or high-fat diet (HFD) for 2-12 weeks and subjected to myocardial ischemia and reperfusion. At four weeks of HFD feeding (pre-diabetes), insulin's cardioprotective effect was significantly blunted compared with the ND group, when insulin signaling molecules were unchanged. However, Cav3/IRβ complex formation, a prerequisite for insulin transmembrane signaling, was significantly reduced. Cav3 tyrosine nitration is prominent in the pre-diabetic heart among various post-translational modifications altering protein/protein interaction. By nitrating cardiomyocytes with SIN-1, signalsome complexes are reduced and insulin transmembrane signalling is blocked. It was determined that Cav3 nitrates at Tyr73 using mass spectrometry. A phenylalanine substitution of Tyr73 (Cav3Y73F) abolished SIN-1 induced Cav3 nitration, restored the Cav3/IRβ complex, and rescued insulin transmembrane signaling. Furthermore, cardiomyocyte-specific Cav3Y73F reexpression blocked HFD-induced Cav3 nitration, preserved Cav3 signalsome integrity, restored transmembrane signaling, and restored insulin's protective effect against ischemic HF in mice. As a result of diabetic nitrative modification at Tyr73 of Cav3, the formation of Cav3/AdipoR1 complexes and the function of adiponectin for cardioprotection are also reduced. Conclusion: In pre-diabetic hearts, nitration of Cav3 at Tyr73 leads to signal complex dissociation that leads to cardiac insulin/adiponectin resistance, contributing to the progression of ischemic heart failure. Developing early interventions geared toward preserving Cav3-centered signalsome integrity may prove effective against diabetic exacerbation of ischemic heart failure. there is no disclosure This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.