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Prenatal exposure of cigarette smoke impacts cardiac regener

Institution: Stanford University
Investigator(s): Ronglih Liao, Ph.D.
Award Cycle: 2018 (Cycle 27) Grant #: 27IP-0046 Award: $596,161
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: High Impact Pilot Award
Abstracts

Initial Award Abstract

Cigarette smoking during pregnancy is detrimental to development, yet remains a pervasive problem in the United States. Tobacco smoke leaves its mark on the genome. The genome consists of genes, messages encoded in DNA, which are transcribed into RNA molecules to be translated into proteins. However, there are RNAs that do not encode proteins, but instead have a role in regulating how other “messenger” RNAs produce proteins. These small “non-coding” RNAs, known as microRNAs, represent an emerging area of study in genetics. MicroRNAs are similar in many species, underscoring their important role in critical cellular functions. MicroRNAs sense environmental stress or danger, capable of quickly affecting how genes function in response to these stressors. Tobacco smoke disrupts the function of microRNAs. Exposure to environmental pollutants, carcinogens, and smoke can affect not only the offspring that were exposed while in utero, but these changes may be transmitted to future generations. We seek to understand the impact of cigarette smoke on cardiac regeneration in neonates exposed in utero and determine the long-term impact on future generations. The heart is capable of regenerating after injury. Lower organisms, like newts, retain this ability throughout life, whereas mammals lose this regenerative capacity in early life. Our laboratory has identified a microRNA, known as miR-34a, which increases during the first week of life in the neonatal mouse and turns off expression of genes necessary for cardiac regeneration. When neonatal mice experience a cardiac injury, such as a surgically-induced heart attack (myocardial infarction), their hearts are capable of fully recovering functionally and structurally. After one week, when miR-34a is expressed, the neonatal mice do not recover, just like adults. Inhibiting miR-34a in adult mice restored cardiac regeneration resulting in less cell death, less scarring (fibrosis), and improved cardiac function. We plan to examine these responses following surgically-induced myocardial infarct in mice exposed in utero to cigarette smoke or filtered air, and in two generations of their offspring (which were not exposed in utero to smoke). We will measure miR-34a and other microRNAs in the heart. This innovative proposal seeks to understand the role of smoking on cardiac regenerative capacity through microRNA disruption, which has not previously been examined. The results of our study will provide evidence for the long-term impact of smoking on future generations, and support the importance of smoking prevention and cessation. Therapeutic targeting of specific microRNA, including miR-34a, could treat cardiac failure due to smoking and have a broad impact on cardiac disease, the leading cause of death in the United States.