| Heart disease is the leading cause of death in the US. It is also a major cause of disability according to the National Institute of Health Heart, Lung, and Blood Institute. A number of factors contribute to myocardial dysfunction and heart disease. In my dissertation research, I studied obesity, pressure overload, starvation and aging-associated compromised cardiac function and cardiac diseases. Among the variety of contributors, obesity is deemed the most important risk factor for heart disease because of its high prevalence. Chronic intake of high-fat diet (HFD) and sedentary life style are the main causes for obesity in both human and animal models. Uncorrected obesity predisposes individuals to myocardial damage characterized as cardiac hypertrophy and contractile dysfunction. Hypertension is also an important risk factor for heart disease. Pressure overload due to hypertension leads to cardiac hypertrophy, which initially acts as an adaptive response to mechanic changes. However, sustained hypertrophic response induces heart failure and contributes to high cardiac morbidity and mortality. In contrast to nutrition overload, starvation can also cause changes in cardiac geometry and function. Furthermore, starvation represents an established model to induce cardiac autophagy, a regulatory process of 'self-eating' of the cells, in mice. Autophagy has been shown to be involved in the onset and development of multiple heart diseases. In addition, cardiac dysfunction and heart diseases can be attributed to cardiac aging, which is accompanied with progressive myocardial remodeling and deteriorated cardiac reserve, and is the reason of increased cardiac morbidity and mortality in elderly.;Cathepsin K belongs to cathepsins family and is a lysosomal cysteine protease. Cathepsin K is highly expressed in bone cells and has been shown to play a critical role in the bone degradation. Consequently, cathepsin K is involved in the development of a number of bone diseases, such as osteoporosis and rheumatoid arthritis. In addition to its role in bone diseases, elevated cathepsin K level has been reported in atherosclerotic plaques, neointimal lesions, and in hypertrophic and failing hearts in both humans and animals. Recent studies revealed an elevation of cathepsin K in adipose tissues of obese humans and mice. Furthermore, inhibition of cathepsin K attenuated body weight gain and serum glucose and insulin levels in obese mice. Besides cathepsin K, other members of cathepsins family, including cathepsin L have also been also implicated in cardiovascular diseases and the development of cardiac hypertrophy. More recent studies have shown that cathepsin L and cathepsin S are capable of regulating autophagy. Interestingly, apoptosis, a process of programmed cell death, has also known to be regulated by members of the cathepsin family. Although more and more studies on cathepsin K are available, most of them focus on bone and there is limited research on the role of cathepsin K in heart disease. In addition, the potential mechanism by which cathepsin K is involved in the pathophysiology of heart function is unclear.;Thus, the overall aim of my PhD dissertation research was to investigate the role of cathepsin K in maintaining cardiac function under different pathological conditions including HFD-induced obesity, pressure overload-induced cardiac hypertrophy, starvation-induced cardiac injury and aging-associated cardiac dysfunction. The underlying molecular mechanisms mediating the effects of cathepsin K on different pathological stresses were also investigated. To achieve this objective, cathepsin K knockout ( Ctsk-/-) mice were used. In the first project, my data revealed that HFD-induced cardiac dysfunction was reconciled in Ctsk-/- mice. Additionally, cathepsin K knockout alleviated whole-body glucose intolerance and improved insulin-signaling in HFD-fed mice. Meanwhile, cathepsin K deficiency prevented HFD-induced apoptosis both in the mouse hearts and in cultured cardiomyocytes. In the second project, I evaluated the role of cathepsin K in pressure overload (abdominal aortic constriction mouse model)-induced cardiac hypertrophy. I found that genetic ablation of cathepsin K mitigated pressure overload-induced cardiac hypertrophy and compromised cardiac function. At the molecular level, cardiac mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinases (Erk) signaling cascades were elevated in the hypertrophic heart, which were blunted by cathepsin K knockout. Using human heart samples, I found that cathepsin K protein levels were significantly elevated in end-stage dilated cardiomyopathy. In the third project, I studied the role of cathepsin K knockout on starvation-induced cardiac dysfunction, with focuses on autophagy and apoptosis pathways. Our results demonstrated that cathepsin K knockout was able to protect against starvation-induced cardiac injury. Our data suggest autophagy and apoptosis were both induced and detrimental for cardiac function under nutrition deprivation. However, cathepsin K knockout by failing to promote autophagic flux attenuated autophagic response to nutrition deprivation. On the other hand, cathepsin K knockout was able to block apoptosis that was activated by starvation suggesting that cathepsin K knockout prevents starvation-induced cardiac injury by inhibiting both the autophagy and apoptosis pathway. Finally, I assessed the effect of cathepsin K knockout on aging-associated heart diseases. These studies revealed that cathepsin K knockout alleviates aging-induced cardiac dysfunction. Cardiac apoptosis was promoted in aging, which was rescued in Ctsk-/- mice. Mechanistic studies suggest that cathepsin K contributed to aging-induced caspase-dependent and -independent apoptosis. Taken together, the studies described in this dissertation provide compelling evidence to suggest that deletion of cathepsin K is beneficial for obesity, pressure overload, starvation and aging-associated heart diseases. Cathepsin K thus represents a novel and valid pharmacological target for the treatment and/or control of heart disease. |
