Lie Gao

Lie GaoAssistant Professor
M.D. 1984, West China University of Medical Sciences
Ph.D. 2001, Peking Union Medical College & Chinese Academy of Medical Sciences
Specialty: Neural control of circulation and autonomic function; pancreatic islet function and diabetes; Skeletal muscle function and exercise intolerance in heart failure.
Major Interest: (1) Regulation of Angiotensin II in the brain and spinal cord on cardiovascular activity and autonomic function in normal and pathologic conditions; (2) Regulation of Angiotensin receptors (AT1R and AT2R) expression during development and disease states; (3) Implication of AT2R in pancreatic islet function and type 2 diabetes; (4) Nrf2 as a potential therapeutic target of skeletal myopathy in chronic heart failure.

Curriculum Vitae

Angiotensin II (Ang II) is an octapeptide hormone essential to various physiological functions. It also plays a critical role in the pathogenesis of many diseases. Ang II exerts effects by binding to two receptors subtypes, the Angiotensin type 1 receptor (AT1R) and type 2 receptor (AT2R), among which AT1R is predominant whereas AT2R’s function is largely masked. In contrast with the AT1R, AT2R was recently acknowledged as the beneficial arm of RSA. Indeed, increasing evidences from animal experiments consistently demonstrated the prevent or therapeutic potential of Compound 21, a non-peptide drug-like AT2R agonist, in several rat models with cardiovascular diseases, including hypertension, heart failure, and stock. During the past two decades, AT2R has been recognized as a developmentally retrogressive receptor highly expressed in embryo and fetus. After birth, this receptor dramatically declines and almost disappears in the mature animal. Opposite to this traditional concept, however, recent evidence from our laboratory indicated a significantly higher AT2R protein expression in adult rats and mice as compared with fetus and neonates. We further found that, in adult rats, brain and pancreas are two key organs richly expressing AT2R protein. Accordingly, our interesting is focusing on the physiological and pathophysiological significance of AT2R in brainstem and pancreas to determine the implication of this receptor in cardiovascular function, sympathetic regulation, and insulin production.

Chronic heart failure (CHF) is one of the leading causes of death in the United States and other industrialized countries. Benefitting from improved medical care, patients with CHF now receive effective treatment and their survival time is remarkably extended. This progress, however, results in more patients with advanced CHF. These patients suffer from skeletal muscle atrophy, a decrease in muscle strength, a lower quality of life, and poor prognosis. Unfortunately, the underlying mechanisms contributing to skeletal muscle dysfunction remain to be elucidated and an effective treatment is lacking. A new interesting of our laboratory is to elucidate the skeletal myopathy in chronic heart failure.

The first objective of this laboratory is to explore the mechanisms underlying the regulation of AT2R in the rostral ventrolateral medullar (RVLM) of brainstem and the intermediolateral column (IML) of spinal cord on cardiovascular activity and sympathetic outflow in normal and chronic heart failure (CHF) states. It is believed that the presympathetic neurons (PSNs) in the RVLM directly participate, and therefore play a crucial role, in the regulation of sympathetic outflow via a monosynaptic projection to the sympathetic preganglionic neurons (SPNs) in the IML of spinal cord. The sympatho-excitation in the CHF state is closely related to the disorders of above neuronal processes in the RVLM and the IML. To clarify these mechanisms we are employing real-time RT-PCR and Western blot analysis to determine gene and protein expression, whole cell patch clamp to measure potassium channels function, extracellular single unit recording to evaluate individual neuron activity, and measurement of arterial blood pressure, heart rate, and renal sympathetic nerve activity to monitor cardiovascular function and sympathetic outflow. These studies are providing novel insights regarding mechanisms of sympatho-excitation in the CHF state from the molecular and genetic level, cellular electrical activity, up to the whole animal physiology and pathophysiology. 

The second objective of this laboratory is to establish the significance of AT2R in pancreatic endocrine regulation. The obtained data from our lab demonstrated that, in pancreatic islets of normal rats, the AT2R functions as the predominant angiotensin receptor subtype to exert a considerable insulinotropic effect. On the other hand, in STZ-induced diabetic rats, activation of AT2R by Compound 21 markedly attenuated hyperglycemia, polyuria, and polydipsia. These therapeutic effects attributed to the protection of Compound 21 on beta cells against STZ toxicity through anti-oxidative and anti-apoptotic mechanisms. Currently, we are exploring the therapeutic potential of Compound 21 in two type 2 diabetic rat models, the Zucker Diabetic Fatty (ZDF) and Goto-Kakizaki (GK) Rats.

The third objective of this laboratory is to determine if the nuclear factor E2-related factor 2 (Nrf2), a key redox-sensitive transcription factor, contributes to skeletal muscle function. We will also evaluate if Nrf2 signaling alters in the skeletal muscle of chronic heart failure and if this altered Nrf2 signaling contributes to the exercise intolerance observed in chronic heart failure.

Recent Publications

  1. Gao J, Zucker IH, Gao L. Activation of central angiotensin type 2 receptors by compound 21 improves arterial baroreflex sensitivity in rats with heart failure. Am J Hypertens. 2014; 27:1248-1256. PMID: 24687998.
  2. Shao C, Yu L, Gao L. B Activation of angiotensin type 2 receptors partially ameliorates streptozotocin-induced diabetes in male rats by islet protection. Endocrinology. 2014; 155:793-804. PMID: 24302627.
  3. Shao C, Zucker IH, Gao L. Angiotensin type 2 receptor in pancreatic islets of adult rats: a novel insulinotropic mediator. Am J Physiol Endocrinol Metab. 2013;305:E1281-1291. PMID: 24085035.
  4. Yu L, Shao C, Gao L. Developmental expression patterns for angiotensin receptors in mouse skin and brain.  J Renin Angiotensin Aldosterone Syst. 2014 Jun; 15(2):139-49.    PMID: 23204186.
  5. Chao J, Gao J, Parbhu KJ, Gao L. Angiotensin type 2 receptors in the intermediolateral cell column of the spinal cord: negative regulation of sympathetic nerve activity and blood pressure. Int J Cardiol. 2013; 168:4046-4055. PMID: 23871345.