Elevated levels of protein phosphatase 1 and phosphatase 2A may contribute to cardiac dysfunction in diabetes

AbstractAlthough protein phosphorylation and dephosphorylation are known to regulate the activities of different enzymes, sufficient information on the role of dephosphorylation in cardiac function is not available. Since protein phosphatases mediate dephosphorylation, it is possible that cardiac dysfunction induced by diabetes may be due to alterations in the activities of these enzymes. We therefore determined cardiac protein phosphatase activity as well as protein contents of phosphatase 1 and phosphatase 2A in diabetic animals. For this purpose, rats were made diabetic by administering a single intravenous injection of streptozotocin (65 mg/kg body weight) and hearts were examined after 1, 2, 3, 4 and 8 weeks. Some of the 4-week diabetic animals received subcutaneous injections of insulin (3 U/day) for a further period of 4 weeks. Cardiac dysfunction was evident after 2 weeks of inducing diabetes and deteriorated further with time. A significant increase in protein phosphatase activity appeared after 1 week and persisted until 8 weeks. Increased protein phosphatase activity in the diabetic heart was associated with a corresponding increase in the protein contents of both phosphatase 1 and phosphatase 2A. Insulin treatment partly prevented the changes observed in diabetic animals. The results suggest that increased protein phosphatase activities and subsequent enhanced protein dephosphorylation may play a role in diabetes-induced cardiac dysfunction

Involvement of protein kinases associated signal transduction mechanisms in cardiac diseases

Protein kinases, a family of enzymes responsible for regulating various cellular processes, have been implicated in the development and progression of various heart diseases, making them attractive therapeutic targets. This review focuses on the role of protein kinases induced phosphorylation and protein phosphatase-induced dephosphorylation in cardiovascular disorders, including heart failure, ischemic heart disease, arrhythmias, hypertension, and diabetic cardiomyopathy. This paper explores the potential of novel kinase-targeted therapies and emerging technologies for the prevention and treatment of these conditions. It also discusses the involvement of protein kinase A (PKA), protein kinase C (PKC), phosphoinositide 3-kinases (PI3Ks), mitogen-activated protein kinases (MAPKs), and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in heart dysfunction and alterations in their function that contribute to their respective cardiac disorders. Furthermore, this article presents a comprehensive overview of protein kinases in cardiac disorders and the potential of innovative kinase-targeted therapies, advanced technologies, and multidisciplinary approaches for the effective prevention and treatment of cardiovascular diseases, ultimately aiming to improve patient outcomes and quality of life

Myosin heavy chain and cardiac troponin T damage is associated with impaired myofibrillar ATPase activity contributing to sarcomeric dysfunction in Ca2+-paradox rat hearts

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Interplay of Oxidative Stress and Necrosis-like Cell Death in Cardiac Ischemia/Reperfusion Injury:A Focus on Necroptosis

Extensive research work has been carried out to define the exact significance and contribution of regulated necrosis-like cell death program, such as necroptosis to cardiac ischemic injury. This cell damaging process plays a critical role in the pathomechanisms of myocardial infarction (MI) and post-infarction heart failure (HF). Accordingly, it has been documented that the modulation of key molecules of the canonical signaling pathway of necroptosis, involving receptor-interacting protein kinases (RIP1 and RIP3) as well as mixed lineage kinase domain-like pseudokinase (MLKL), elicit cardioprotective effects. This is evidenced by the reduction of the MI-induced infarct size, alleviation of myocardial dysfunction, and adverse cardiac remodeling. In addition to this molecular signaling of necroptosis, the non-canonical pathway, involving Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-mediated regulation of mitochondrial permeability transition pore (mPTP) opening, and phosphoglycerate mutase 5 (PGAM5)–dynamin-related protein 1 (Drp-1)-induced mitochondrial fission, has recently been linked to ischemic heart injury. Since MI and HF are characterized by an imbalance between reactive oxygen species production and degradation as well as the occurrence of necroptosis in the heart, it is likely that oxidative stress (OS) may be involved in the mechanisms of this cell death program for inducing cardiac damage. In this review, therefore, several observations from different studies are presented to support this paradigm linking cardiac OS, the canonical and non-canonical pathways of necroptosis, and ischemia-induced injury. It is concluded that a multiple therapeutic approach targeting some specific changes in OS and necroptosis may be beneficial in improving the treatment of ischemic heart disease

Mechanisms for the Defects in Phospholipid Signal Transduction in Diabetic Cardiomyopathy

431-440Although diabetic cardiomyopathy is associated with heart dysfunction and disturbance in cardiac sarcolemmal membrane phospholipid composition, the role of the different phospholipases and their related signaling mechanisms to altered function of the heart in diabetes is not completely understood. Thus, understanding the pathophysiology of cardiovascular abnormalities in diabetes, as well as identifying defects in various components of the phospholipid signaling pathways, that could serve as therapeutic targets, is warranted. Accordingly, this review provides an outline of the role of and the mechanisms for the defects in phospholipase A2, C and D-mediated signal transduction in the diabetic heart. In addition, the potential of different phospholipases as targets for drug development for the prevention/treatment of heart disease in diabetes is discussed. </span