Loss of PKA regulatory subunit 1α aggravates cardiomyocyte necrosis and myocardial ischemia/reperfusion injury

Abstract

Reperfusion therapy, the standard treatment for acute myocardial infarction, can trigger necrotic death of cardiomyocytes and provoke ischemia/reperfusion (I/R) injury. However, signaling pathways that regulate cardiomyocyte necrosis remain largely unknown. Our recent genome-wide RNAi screen has identified a potential necrosis suppressor gene PRKAR1A , which encodes PKA regulatory subunit 1α (R1α). R1α is primarily known for regulating PKA activity by sequestering PKA catalytic subunits in the absence of cAMP. Here, we showed that depletion of R1α augmented cardiomyocyte necrosis in vitro and in vivo , resulting in exaggerated myocardial I/R injury and contractile dysfunction. Mechanistically, R1α loss downregulated the Nrf2 antioxidant transcription factor and aggravated oxidative stress following I/R. Degradation of the endogenous Nrf2 inhibitor Keap1 through p62-dependent selective autophagy was blocked by R1α depletion. Phosphorylation of p62 at Ser349 by mammalian target of rapamycin complex 1 (mTORC1), a critical step in p62-Keap1 interaction, was induced by I/R, but diminished by R1α loss. Activation of PKA by forskolin or isoproterenol almost completely abolished hydrogen-peroxide-induced p62 phosphorylation. In conclusion, R1α loss induces unrestrained PKA activation and impairs the mTORC1-p62-Keap1-Nrf2 antioxidant defense system, leading to aggravated oxidative stress, necrosis, and myocardial I/R injury. Our findings uncover a novel role of PKA in oxidative stress and necrosis, which may be exploited to develop new cardioprotective therapies.

Insulin-Induced Cardiomyocytes Hypertrophy That Is Prevented by Taurine via β-alanine-Sensitive Na+-Taurine Symporter

“…Among these proteins, all the calcium-dependent signaling, such as phosphorylation of the L-type calcium channel, increases its probability of opening and increases calcium influx through this type of channel [51][52][53]. Furthermore, the catalytic subunit of PKA will also regulate the activity of the potassium channels [54] and other mechanisms [55]. Increased intracellular calcium will activate several signaling and transcriptional factors and genes implicated in cardiomyocyte hypertrophy [11].…”

The Interplay between Autophagy and Redox Signaling in Cardiovascular Diseases

“…The changes in redox homeostasis can also regulate autophagy, which may have role in adaptive myocardial responses to disease triggers or maladaptive responses involving cell death induction. In several cardiovascular diseases, a direct interplay between autophagy and redox signaling has been documented [ 8 , 29 , 30 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ]. In Table 1 , several examples documenting the interplay between autophagy and Nrf2 in heart failure, ischemic heart disease, and cardiomyopathies are presented.…”

“…Interestingly, Nrf2 can also promote the autophagic degradation of toxic ubiquitinated proteins by providing a protective effect against cardiac proteotoxicity [ 30 ]. The antioxidant defense system formed by p62-Keap1-Nrf2 plays a role here, and the regulatory function of this system has been described in myocardial responses to pathological conditions [ 147 , 155 ]. Free radicals can induce Nrf2-mediated transcription of p62 and autophagy.…”

Programmed Cell Death: Complex Regulatory Networks in Cardiovascular Disease

“…Oerlemans et al demonstrated that RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL) expression was up-regulated in the myocardium after reperfusion, and the necrosis inhibitor Necrostatin-1 could reduce the phosphorylation levels of RIPK1 and RIPK3 and the recruitment of MLKL, thus inhibiting cell necrosis and reducing myocardial infarct size (Oerlemans et al, 2012). Currently, I/R models are preferred to elucidate the effect of different factors on cardiomyocyte necrosis through various pathways such as mechanistic target of rapamycin (mTOR), rate-oxygenation (ROX) and MLKL (Supplementary Table S2) (Yang et al, 2018a;She et al, 2019;Chen et al, 2020;Jiang et al, 2021c;Han et al, 2021;Liu et al, 2021;Pullaiah et al, 2021;Zhang et al, 2021).…”